research progress of bile acids in cancer

Research Progress of Bile Acids in Cancer

Affiliations.

• 1 Central Laboratory, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
• 2 Department of Hepatobiliary and Pancreatic Surgery, Affiliated Jinhua Hospital, Zhejiang University School of Medicine, Jinhua, China.
• PMID: 35127481
• PMCID: PMC8810494
• DOI: 10.3389/fonc.2021.778258

Bile acids (BAs) were originally known as detergents to facilitate the digestion and absorption of lipids. And our current knowledge of BAs has been extended to potential carcinogenic or cancer suppressor factors due to constant research. In fact, BAs were regarded as a tumor promoters as early as the 1940s. Differential bile acid signals emitted by various bile acid profiles can produce distinct pathophysiological traits, thereby participating in the occurrence and development of tumors. Nevertheless, in recent years, more and more studies have noticed the value of BAs as therapeutic targets. And several studies have applied BAs as a therapeutic agent for various diseases including cancer. Based on the above evidence, we acknowledge that the role of BAs in cancer has yet to be exploited, although considerable efforts have been made to probe the functions of BAs. In this review, we describe the characteristics of BAs as a double-edged sword in cancer, hoping to provide references for future cancer treatments.

Keywords: angiogenesis; bile acids; cancer; inflammation and immunity; metastasis; proliferation and death.

Copyright © 2022 Fu, Yu, Xu and Yu.

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• Published: 26 December 2022

A bile acid-related prognostic signature in hepatocellular carcinoma

• Wang Zhang 1   na1 ,
• Yue Zhang 1   na1 ,
• Yipeng Wan 1 ,
• Qi Liu 1 &
• Xuan Zhu 1  

Scientific Reports volume  12 , Article number:  22355 ( 2022 ) Cite this article

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• Gastroenterology

Due to the high mortality of hepatocellular carcinoma (HCC), its prognostic models are urgently needed. Bile acid (BA) metabolic disturbance participates in hepatocarcinogenesis. We aim to develop a BA-related gene signature for HCC patients. Research data of HCC were obtained from The Cancer Genome Atlas (TCGA) and International Cancer Genome Consortium (ICGC) online databases. After least absolute shrinkage and selection operator (LASSO) regression analysis, we developed a BA-related prognostic signature in TCGA cohort based on differentially expressed prognostic BA-related genes. Then, the predictive performance of the signature was evaluated and verified in TCGA and ICGC cohort respectively. We obtained the risk score of each HCC patient according to the model. The differences of immune status and drug sensitivity were compared in patients that were stratified based on risk score. The protein and mRNA levels of the modeling genes were validated in the Human Protein Atlas database and our cell lines, respectively. In TCGA cohort, we selected 4 BA-related genes to construct the first BA-related prognostic signature. The risk signature exhibited good discrimination and predictive ability, which was verified in ICGC cohort. Patients were classified into high- and low-risk groups according to their median scores. The occurrence of death increased with increasing risk score. Low-risk patients owned favorable overall survival. High-risk patients possessed high immune checkpoint expression and low IC50 values for sorafenib, cisplatin and doxorubicin. Real-time quantitative PCR and immunohistochemical results validate expression of modeling genes in the signature. We constructed the first BA-related gene signature, which might help to identify HCC patients with poor prognosis and guide individualized treatment.

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Hepatocellular carcinoma

Identifying therapeutic targets for cancer among 2074 circulating proteins and risk of nine cancers

Introduction.

Worldwide, liver cancer ranks as the sixth most common cancer 1 . In Asia, the disease is the fifth most prevalent tumor 2 . More than 800,000 new cases of liver cancer are detected each year globally 3 , which reflects that liver cancer is a major global health problem. Cases of hepatocellular carcinoma (HCC) comprise approximately 90% of primary liver cancer cases 4 . The early diagnosis of HCC remains a challenge because of insidious and nonspecific symptoms at an early phase. Consequently, most patients are detected in advanced HCC with metastasis, which negates the opportunity for radical surgery and results in an unfavorable prognosis. Although tremendous advances have been achieved in the diagnosis and therapeutic strategy for HCC over the past decades, patients with HCC have an unsatisfactory prognosis. Therefore, developing and validating novel reliable prognostic models for HCC are of great importance for identifying patients with poor prognosis and making reasonable clinical decisions.

Bile acids (BAs) are the main constituents of bile. In the liver, cholesterol is converted into BAs through a series of chemical reactions. The human bile acid (BA) pool is composed of a large portion of primary BAs and a small portion of secondary BAs. Primary BAs are transformed into secondary BAs via deconjugation and 7α-dehydroxylation reactions with the help of gut microbiota 5 . Maintaining BA homeostasis is critical to normal liver function. In addition to their physiological role in intestinal lipid absorption, BAs function as endogenous signaling molecules that regulate multiple metabolic, inflammatory and immune processes 6 , 7 , 8 . Moreover, BAs are involved in the occurrence of multitudinous gastrointestinal carcinomas 9 , 10 . The biological processes of BA synthesis and metabolism are complicated and are regulated by various bile acid-related genes (BAGs). Consistent with BAs, BAGs are closely tied to the pathogenesis of HCC. SLC27A5, a fatty acid transporter-encoding gene, is essential for BA reconjugation 11 . SLC27A5 knockout facilitates lipid peroxidation and thereby contributes to NRF2/TXNRD1 pathway activation, which promotes HCC progression. This outcome indicates that SLC27A5 serves as a tumor suppressor 12 . FGF19 is a dietary-responsive endocrine hormone essential for enterohepatic circulation of BAs 13 . Abnormal expression of FGF19-FGFR4 has been shown to accelerate hepatocarcinogenesis and metastasis, while inhibition of the FGF19/FGFR pathway augments tumor-suppressive activity and improves the prognosis in patients with HCC 14 , 15 . In summary, the role of BAGs in hepatic carcinogenesis and prognosis is variable and worthy of further research.

Here, we developed the first BA-related prognostic signature based on these differentially expressed prognostic BAGs in HCC patients from The Cancer Genome Atlas (TCGA) cohort. In International Cancer Genome Consortium (ICGC) cohort, we verified the predictive performance of the signature. Additionally, we probed into the role of the signature in forecasting drug susceptibility.

Materials and methods

Data acquisition.

Research data of HCC were obtained from TCGA ( https://portal.gdc.cancer.gov ) and ICGC ( https://dcc.icgc.org/ ) online databases. In TCGA database, we obtained sequencing data of 374 HCC samples and 50 normal samples. After matching with clinical data, 370 HCC patients were included. In ICGC database, the transcriptome data and corresponding clinicopathological data of 232 HCC patients were obtained. BAGs were collected from the Gene Set Enrichment Analysis (GSEA) database ( http://www.gsea-msigdb.org/gsea/index.jsp ) using “bile acid” as the main search term, and 23 BA-related gene sets were found. These gene sets were comprised of genes that participate in BA biosynthesis, secretion, metabolism, and BA-related signaling pathways. After removing the overlapping genes, 199 BAGs were obtained. TCGA expression matrix did not contain the expression of MIR6886. Therefore, 198 BAGs were collected for further analysis and are displayed in Table S1 . Figure S1 display the analysis flow of this study.

Identification of differentially expressed prognostic BAGs

In TCGA cohort, we used p < 0.05, |log2 fold change (FC)|> 1 as standard to differentiate the differentially expressed BAGs between the normal group and the HCC group. The differentially expressed BAGs were displayed with a heatmap using “pheatmap” package in R4.1.2. Univariate Cox analysis was conducted to screen significantly prognostic BAGs after the expression data for the BAGs were combined with TCGA survival data. Subsequently, we intersected the differentially expressed BAGs with the prognostic BAGs to identify the differentially expressed prognostic BAGs for further analysis.

Construction and validation of the gene signature

Based on the differentially expressed prognostic BAGs, we developed a risk model by using least absolute shrinkage and selection operator (LASSO) regression analysis. After LASSO regression analysis, 4 differentially expressed prognostic BAGs and its regression coefficients were obtained and were chosen for model building. Then, patient risk score was calculated with the following equation: Risk score = (Expression value of BAG1) * Coefficient 1 + (Expression value of BAG2) * Coefficient 2 + … + (Expression value of BAGn) * Coefficient n. According to the median risk score, we divided HCC cases into high- and low-risk groups. The discrimination ability of the signature was evaluated by principal component analysis (PCA). We utilized the area under the curve (AUC) to evaluate the prediction ability of gene signature.

Functional enrichment analysis

GSEA, Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses were performed with the “clusterProfiler” package in R4.1.2. To evaluate the infiltration of various immune cells and the activity levels of diverse immune-related pathways in each HCC sample, we conducted single-sample gene set enrichment analysis (ssGSEA).

Tumor mutation burden and drug sensitivity analysis

Tumor mutation burden (TMB) scores were calculated and gene mutations were visualized via the “Maftools” package, which is easy to use and contains multiple statistical and computational approaches for cancer genome research 16 . According to patient gene expression data, the clinical chemotherapeutic response of patient can be accurately predicted by using the “pRRophetic” package 17 . The semi-inhibitory concentration (IC50) is a useful indicator of drug sensitivity and refers to the drug concentration required for 50% cell proliferation suppression in vitro. Therefore, a high IC50 indicates a low sensitivity of neoplastic cells to the drug. We predicted the drug sensitivities of HCC patients by using the pRRophetic package.

Cell culture and real-time quantitative PCR analysis (RT–qPCR)

Human hepatocyte cell line LO2 and HCC cell line HepG2 were maintained in RPMI 1640 (Gibco, USA) and DMEM (DMEM, Gibco, USA), respectively. Complementary DNA was obtained by reverse transcription of total cellular RNA with a TIANScript RT kit (Tiangen, China). Quantitative PCR was carried out with 2× M5 HiPer UltraSYBR Mixture (Mei5bio, China). GAPDH was served as an internal control. PCR primers are displayed in Table S2 .

Statistical analysis

R4.1.2 software and SPSS 20.0 were applied to statistical analyses. P < 0.05 was considered statistically significant.

Clinicopathological features of the included HCC patients

We initially analyzed the clinicopathological features of the HCC patients in this study. In TCGA cohort, 370 HCC patients with clinicopathological data were used for model building and survival analysis. 232 HCC patients derived from ICGC database were served as a validation cohort. The Clinicopathological features of HCC patients in this study are shown in Table 1 . In TCGA and ICGC cohorts, most patients were male, with older than 60 years, no family history. In TCGA cohort, part of HCC patients had liver fibrosis or cirrhosis (137/370, 37.03%). The main HCC risk factor in medical history is alcohol intake.

Identification and functional enrichment analysis of the differentially expressed BAGs

Before constructing the prognostic signature, we screened the differentially expressed BAGs and analyzed the potential roles of these genes in hepatocarcinogenesis. 198 BAGs obtained from 23 BA-related gene sets were included in the differentially expressed analysis of TCGA cohort. We identified 44 genes as differentially expressed BAGs between the normal and tumor groups (Table S3 ). As shown in Fig.  1 A, most of the differentially expressed BAGs were upregulated in the HCC samples. To explore the potential mechanism by which these genes contribute to HCC, GO and KEGG analyses were carried out. According to biological process (BP) analysis, Steroid metabolism, BA metabolism, BA and bile salt transport were significantly enriched. As indicated by cellular component (CC) analysis, these differentially expressed BAGs were significantly concentrated in peroxisomes and microbodies. Lipid, BA and monocarboxylic acid transmembrane transporter activity were significantly enriched categories according to GO molecular function (MF) analysis (Fig.  1 B). KEGG ( https://www.kegg.jp/ ), an integrated database, establishes the connection between genomic information and higher order functional information, which contributes to the functional annotation of genes and proteins 18 , 19 . KEGG analysis was carried out to explore the pathway enrichment of differentially expressed BAGs, which is useful for understanding the functions of the genes. As indicated by KEGG analysis, the pathways involved with primary BA biosynthesis and bile secretion were enriched (Fig.  1 C).

Differentially expressed BAGs and functional enrichment analyses based on TCGA cohort. ( A ) Heatmap of differential BAGs. The heatmap was created by using “pheatmap” package in R4.1.2 ( https://www.r-project.org/ ). ( B ) GO analysis of differential BAGs. ( C ) KEGG analysis of differential BAGs.

Construction of the BA-related risk signature in TCGA cohort

In order to constructed a BA-related risk signature in TCGA cohort, the prognostic BAGs were first screened by univariate Cox analysis from 198 BAGs with the criteria of P < 0.05. We identified 61 genes as significantly prognostic BAGs, and these genes are displayed in Table S4 . Subsequently, 17 differentially expressed prognostic BAGs were obtained by intersecting the 44 differentially expressed BAGs with the 61 prognostic BAGs (Fig.  2 A). We subjected the common differentially expressed genes (DEGs) that we have obtained from intersection of differentially expressed BAGs with the prognostic BAGs to feature selection—LASSO regression method to select only those genes which are very relevant to formulate a bile acid-related prognostic signature (Fig.  2 B and C). Finally, 4 BAGs were selected for model building. The 4 BAGs and its regression coefficients are displayed in Table S5 . The correlation network indicated that AKR1D1 had a negative relationship with other modeling genes (Fig. S2 ). As shown in Figs.  2 D and S3A–3D , AKR1D1 was protective factor for overall survival, while the others were risk factors based on the univariate Cox analysis. In addition, AKR1D1 was upregulated, while the others were downregulated in the normal samples (Fig. S4A–4D ). Based on the 4 modeling genes and its regression coefficients, the equation for calculating the patient risk score was obtained and was as follows: Risk score = (Expression value of AKR1D1)*(− 0.0045) + (Expression value of NPC1) * 0.2253 + (Expression value of FABP6) * 0.1733 + (Expression value of MAPK3) * 0.0230. In TCGA cohort, patients were classified into high- and low-risk groups according to their median scores (Fig.  2 E). The occurrence of death tended to increase with increasing risk score, which was further confirmed by survival analysis (Fig.  2 F, G). The two groups were different in the expression of the modeling genes (Fig.  2 H). The risk signature exhibited good discriminability and predictive ability (Fig.  2 I and J).

Construction of the bile acid-related risk signature in TCGA cohort. ( A ) Venn diagram displaying 17 intersecting genes between the 44 differentially expressed BAGs and 61 prognostic BAGs. ( B ) LASSO regression analysis of 17 differentially expressed prognostic BAGs. ( C ) Cross-validation of LASSO regression analysis. ( D ) Forest plot of modeling genes. ( E ) Risk grouping based on median risk value. ( F ) Relationship between risk value and survival status. ( G – I ) KM curve, expression of modeling genes and PCA based on risk grouping. ( J ) ROC curves in TCGA cohort.

Validation of the BA-related risk signature in ICGC cohort

The model possessed good predictive performance in TCGA cohort. We then verified the predictive performance of the signature in external validation cohort. In ICGC cohort, we obtained patient risk scores with the above equation. Then, high- and low-risk patients were distinguished with the same median scores (Fig.  3 A). Figure  3 B shows an increase in mortality with increasing risk score. Kaplan–Meier (KM) plot further confirmed that high risk value hinted unfavorable overall survival (Fig.  3 C). In high-risk patients, increased levels of the modeling genes were observed except AKR1D1 (Fig.  3 D). The signature also displayed good differentiating capacity and predictive power in the external validation cohort (Fig.  3 E and F).

Verification of the bile acid-related risk signature in ICGC cohort. ( A ) Risk grouping based on TCGA median risk value. ( B ) Correlation between risk value and survival status. ( C – E ) KM curve, expression of modeling genes and PCA based on risk grouping. ( F ) ROC curves in ICGC cohort.

Independent predicting power of BA-related model

We subsequently explored whether the risk score was independent prognostic factor for HCC patients. After merging risk score with clinicopathological characteristics, independent prognostic factors were identified with Cox regression analysis. The prognosis of TCGA and ICGC patients was impacted by risk score and tumor stage, which revealed by univariate Cox regression analysis in Fig.  4 A and C. Risk score manifested independent predicting power for unfavorable survival, which corroborated by multivariate Cox regression analysis in Fig.  4 B and D.

Independent predicting power of BA-related model. ( A , B ) Forest plots of Cox regression analysis results in TCGA cohort. ( C , D ) Forest plots of Cox regression analysis results in ICGC cohort.

Risk score-related clinicopathological features

In order to understand the correlation between the model and clinicopathological features, we explored the discrepancy in risk score among patients with different clinicopathological features in TCGA and ICGC cohorts. We discovered risk score increased with increasing HCC severity. In TCGA cohorts, patients grading severity aligned with risk score (Fig.  5 A). High risk scores were observed in patients with stage III–IV (Fig.  5 B and C). Other clinicopathological parameters, including age, gender, prior malignancy and cancer history, did not correlate significantly with the risk score (Fig. S5A–5F ).

Risk score-related clinicopathological features. ( A , B ) Grade and stage in TCGA cohort. ( C ) Stage in ICGC cohort.

Functional enrichment analyses based on risk score

According to the previous results, patient outcome varies with risk score. Whereafter, we conducted functional enrichment analyses to explore the possible mechanisms that contributed to this phenomenon. Based on risk grouping, we screened 219 genes as differential genes with the criteria of P < 0.05 and |log2FC|> 1 (Table S6 ). Subsequently, we conducted GO and KEGG enrichment analyses with clusterProfiler package. According to BP analysis, organic acid and steroid metabolism was significantly enriched. As indicated by CC analysis, these genes were significantly centralised in lipoprotein particles and protein-lipid complexes. In MF analysis, oxidoreductase activity and arachidonic acid monooxygenase activity were enriched (Fig.  6 A). According to KEGG analysis, the pathways linked with complement and coagulation cascade, chemical carcinogenesis and bile secretion were concentrated (Fig.  6 B). The pathways correlated with cell cycle and tumorigenesis were upregulated while the pathways correlated with drug metabolism and primary BA biosynthesis were downregulated in high-risk patients, as revealed by the GSEA (Fig.  6 C).

GO and KEGG analyses and GSEA based on risk grouping in TCGA cohort. ( A – C ) Results of GO analysis, KEGG analysis and GSEA.

Risk score-related immune status

The immune microenvironment plays an essential role in hepatocarcinogenesis, therefore, we conducted ssGSEA to evaluate the immune status. In high-risk patients, the proportions of activated dendritic cells (aDCs), macrophages and Tregs were increased, while the infiltration of natural killer (NK) cells exhibited the opposite trend (Fig.  7 A). In low-risk patients, high scores of cytolytic activity and IFN response were observed (Fig.  7 B). Patients with high immune checkpoint expression benefit more from immune checkpoint inhibitor therapy. Therefore, we evaluated the immune checkpoint expression in HCC patients. In our study, High-risk patients owned high immune checkpoint expression (Fig.  7 C–H).

Risk score-related immune status. ( A , B ) Results of ssGSEA. ( C – H ) immune checkpoint expression based on risk grouping. *P < 0.05, ** P < 0.01, *** P < 0.001, ns, not significant.

Differences in TMB and drug sensitivity based on risk grouping

TMB reflects the quantity of the somatic mutation in tumor tissues, which has a close relationship with response to immunotherapy and is considered as a promising immune-response biomarker 20 , 21 . Therefore, we assessed the TMB in HCC patients with different risk scores. Top 20 mutated genes were visualized by waterfall plots (Fig.  8 A and B). TP53 is the most mutated gene in high-risk group. The mutation frequency of TP53 in high-risk group is 42% and the main mutation type is missense mutation. In low-risk group, CTNNB1 is the most frequently mutated gene and its mutation type is predominantly missense mutation. High-risk patients tend to have higher TMB (Fig.  8 C). Drug resistance not only influences the therapeutic effect but also shortens patient survival. The prediction of drug sensitivity is a vital component in individual treatment. Thus, we evaluated the difference in drug sensitivity based on risk grouping. In high-risk patients, we found significantly low IC50 values for sorafenib, cisplatin and doxorubicin (Fig.  8 D–F), which meant these drugs were more effective for these patients. The high- and low-risk patients had same sensitivity to mitomycin (Fig. S6 ).

Differences in TMB and drug sensitivity based on risk grouping. ( A , B ) Waterfall plots of mutant genes. ( C ) TMB based on risk grouping. ( D – F ) The sensitivity comparisons of sorafenib, cisplatin and doxorubicin based on risk grouping.

Validation of the modeling genes

According to the previous analyses, modeling genes are expressed differently in normal and tumor samples. We subsequently validated the protein and mRNA levels of the modeling genes in the Human Protein Atlas database and our cell lines, respectively. Compared with hepatocyte cell line LO2, HCC cell line HepG2 had higher mRNA expression levels of NPC1, FABP6 and MAPK3, which was consistent with the bioinformatic analysis results (Fig.  9 A–C). Elevated mRNA levels of AKR1D1 were verified in LO2 cells (Fig.  9 D). In the Human Protein Atlas database, we verified the protein expression of 4 modeling genes. High levels of MAPK3 protein expression were observed in HCC samples, while AKR1D1 protein expressions were upregulated in normal tissues. FABP6 was not detected in normal or HCC samples (Fig. S7A–D ).

Verification of modeling genes in our cell lines. ( A ) NPC1, ( B ) FABP6, ( C ) MAPK3, ( D ) AKR1D1.

The pathogenesis of HCC is extremely complicated and not fully understood. BAGs not only regulate the synthesis and metabolism of BAs but also play important roles in hepatocarcinogenesis. At present, most research focuses on the effect of a single BA gene on the biological behavior and prognosis of HCC. Considering the multiple impacts of BAGs on hepatocarcinogenesis, we constructed the first prognostic signature of BAGs to distinguish high-risk patients and guide personalized treatment.

44 differentially expressed BAGs were identified between normal and HCC samples based on 198 BAGs collected from 23 BA-related gene sets. Unsurprisingly, these genes were significantly concentrated in BA synthesis metabolism, which confirmed by functional enrichment analyses. Then the first BA-related prognostic signature was constructed based on 4 differentially expressed prognostic BAGs after a systematic analysis. Subsequently, we calculated patient risk scores with this signature. The risk signature exhibited good discriminability and predictive ability according to PCA, receiver operating characteristic (ROC) and KM curve analysis. Risk score manifested independent predicting power for unfavorable survival. In addition, we validated not only the predictive value and stability of genetic model but also the expression levels of modeling genes.

The model we constructed contained 4 differentially expressed prognostic BAGs, namely, NPC1, FABP6, MAPK3 and AKR1D1. NPC1 encodes the membrane protein Nieman-Pick C1 (NPC1), which is critical for cholesterol export from lysosomes/late endosomes 22 . NPC1 mutation results in a life-limiting lysosomal storage disease, Niemann-Pick disease type C, and increases the risk of hepatocarcinogenesis 23 , 24 . FABP6 is a BA transporter in ileal epithelial cells and is critical for the enterohepatic circulation of BAs 25 . FABP6 also participates in the progression of numerous types of cancer 26 , 27 , 28 . Compared with adjacent normal liver tissues, overexpressed FABP6 was observed in HCC tissues 29 . Consistent with this, we obtained similar results in our study. However, the specific mechanisms of FABP6 in HCC need to be further studied. MAPK3, also known as extracellular signal-regulated kinase 1 (ERK1), is a member of the MAPK signaling pathway, which participates in tumorigenesis and metastasis in multiple tumor types 30 . ERK1, together with ERK2, plays an important role in BA metabolism. BAG expression profile was altered in ERK1/2 knockout mice. ERK1/2 knockout decreased the expression of BA uptake genes and increased the expression of BA export gene 31 . CYP7A1 serves as a rate-limiting enzyme to participate in BA biosynthesis 32 . In human hepatocytes, ERK1/2 negatively regulated the expression of CYP7A1 and fibroblast growth factor 19 inhibited CYP7A1 expression partially through activation of ERK1/2 33 . In the pathogenesis of HCC, ERK1, but not ERK2, phosphorylated intestine-specific homeobox, resulting to its nuclear translocation and the expression of downstream genes related to cell proliferation, malignant transformation and the resistance to sorafenib 34 . The expression and activation of MAPK3 were upregulated in HCC tissues and cells 35 , 36 . In line with this, our results indicated that MAPK3 were highly expressed in HCC. In addition, MAPK3 was risk factors for overall survival. Delta(4)-3-Ketosteroid 5-Beta-Reductase encoded by AKR1D1 acts as one of the key reductases related to BA biosynthesis 37 . Aberrant expression of AKR1D1 contributes to BA synthesis defect, metabolic disorders and liver failure 38 , 39 , 40 . In human hepatoma cells, AKR1D1 regulated glucocorticoid clearance and the activation of the glucocorticoid receptor 41 . Overexpression of AKR1D1 significantly inhibited the cell viability and the activation of androgen receptor signaling pathway in HCC cell 42 . Low expression of AKR1D1 was observed in HCC tissue 43 . Here, HCC patients with elevated AKR1D1 had favorable prognosis, indicating that AKR1D1 might have an antitumor effect in HCC. AKR1D1 also had a good diagnostic ability for HCC 42 . Our model might be useful to guide the diagnosis of HCC and the genes included in our model might serve as promising diagnostic biomarkers for HCC. Further studies are warranted.

Tumor immune microenvironment influences hepatocarcinogenesis and treatment strategies for patients 44 . BAs not only play an essential role in intestinal lipid absorption but also modulate immunity 6 , 45 . Therefore, we conducted ssGSEA to evaluate the immune status. In high-risk patients, the proportions of aDCs, macrophages and Tregs were increased, while the infiltration of NK cells exhibited the opposite trend. In low-risk patients, high score of IFN response was observed. In HCC patients, Treg intratumoral accumulation triggered by intratumoral macrophages suppresses tissue-derived CD4+ CD25− T cells activation, which contributes to HCC progression and unfavorable prognosis 46 . In addition, Tregs inhibit CD8+ T cells proliferation and activation in HCC patients 47 . NK cells form nearly half of the liver's lymphocytes. In HCC microenvironment, a high abundance of NK cells in HCC tissue is a favorable factor for survival 48 . Via a STAT3-dependent pathway, IFNs induce HCC cell apoptosis through blocking β-catenin signaling pathway 49 . Impaired antitumor immunity may contribute to adverse prognosis in high-risk patients.

Immune checkpoint inhibitors (ICIs) are new and effective treatment choices for HCC patients. However, as with other drugs, not all patients are similarly sensitive to ICIs. Distinguishing the ICI-sensitive population is important to individualized therapy. The interaction of immune checkpoint proteins with their ligands leads to T cells inactivation and immunosuppression. As monoclonal antibodies, ICIs can block the process by binding with immune checkpoint proteins, thus restoring T cell activation and immune attack 50 . ICIs might have better effects on high-risk patients who have upregulated expression levels of common immune checkpoint. TMB is a significant indicator of genomic stability 51 . Tumor with high TMB can generate more neoantigens, some of which can serve as signals to induce immune system activation and T-cell reactivity, thus increasing sensitivity of tumor cells to immunotherapy 52 , 53 . Therefore, TMB is an emerging biomarker for predicting ICIs response, and ICIs possess better effects in patients with a high TMB 54 . In our study, high TMB was discovered in high-risk patients. Chemotherapy is an important component in comprehensive treatment of advanced HCC. Predicting chemotherapeutic drug sensitivity is of great significance to individualized therapy. The gene expression may act as a surrogate for unmeasured phenotypes that are directly relevant to chemotherapeutic sensitivity, which provides the possibility to predict chemotherapeutic sensitivity based on gene expression 55 . Many researchers use gene expression data to predict drug sensitivity, including chemotherapeutic agents 56 , 57 . In our study, we evaluated the sensitivity to some chemotherapeutic and targeted drugs in HCC patients. Our results revealed that low IC50 values for sorafenib, cisplatin and doxorubicin were observed in high-risk patients, which indicated that high-risk patients responded better to sorafenib, cisplatin and doxorubicin. Therefore, our gene signature provides the basis for the individualized application of ICIs and contributes to guide individualized chemotherapy and targeted therapy.

Undeniably, there are some drawbacks in our study. First, the exact mechanisms of modeling genes in hepatocarcinogenesis have not been explored, and thus, further studies are needed. Second, the risk signature was constructed and verified based on public databases. The 95% confidence intervals of the risk scores were somewhat wide in the Cox regression analyses, and the AUC for the ICGC cohort was larger than that for the TCGA cohort, which might be partly attributed to the divergent risk factors and pathogenesis of HCC in different regions. Therefore, a larger, multicenter cohort is demanded to further test the predictive capability of risk signature.

Conclusions

In conclusion, we constructed the first BA-related gene signature, which presented a promising prediction performance and may be useful for making reasonable clinical decisions for HCC patients.

Data availability

The data analyzed in the current study are freely available in the TCGA ( https://portal.gdc.cancer.gov ), ICGC ( https://dcc.icgc.org/ ) and Gene Set Enrichment Analysis ( http://www.gsea-msigdb.org/gsea/index.jsp ) databases.

Abbreviations

The Cancer Genome Atlas

International Cancer Genome Consortium

Bile acid-related genes

Gene Set Enrichment Analysis

Least absolute shrinkage and selection operator

Log2 fold change

Principal component analysis

Area under the curve

Gene Ontology

Kyoto Encyclopedia of Genes and Genomes

Single-sample gene set enrichment analysis

Tumor mutation burden

Semi-inhibitory concentration

Real-time quantitative PCR

Biological process

Cellular component

Molecular function

Differentially expressed genes

Kaplan–Meier

Activated dendritic cells

Natural killer

Receiver operating characteristic

Extracellular signal-regulated kinase 1

Immune checkpoint inhibitors

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Acknowledgements

We would like to thank Guozi teacher for technical support.

This work was supported by the “Gan-Po Talent 555” project of Jiangxi Province [No. GCZ(2012)-1] and the National Natural Science Foundation of China (No. 81960120).

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Department of Gastroenterology, Jiangxi Clinical Research Center for Gastroenterology, First Affiliated Hospital of Nanchang University, Nanchang, China

Wang Zhang, Yue Zhang, Yipeng Wan, Qi Liu & Xuan Zhu

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The role of bile acids in carcinogenesis

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• Damjana Rozman 1 ,
• Tünde Kovács 2 , 3 ,
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Bile acids are soluble derivatives of cholesterol produced in the liver that subsequently undergo bacterial transformation yielding a diverse array of metabolites. The bulk of bile acid synthesis takes place in the liver yielding primary bile acids; however, other tissues have also the capacity to generate bile acids (e.g. ovaries). Hepatic bile acids are then transported to bile and are subsequently released into the intestines. In the large intestine, a fraction of primary bile acids is converted to secondary bile acids by gut bacteria. The majority of the intestinal bile acids undergo reuptake and return to the liver. A small fraction of secondary and primary bile acids remains in the circulation and exert receptor-mediated and pure chemical effects (e.g. acidic bile in oesophageal cancer) on cancer cells. In this review, we assess how changes to bile acid biosynthesis, bile acid flux and local bile acid concentration modulate the behavior of different cancers. Here, we present in-depth the involvement of bile acids in oesophageal, gastric, hepatocellular, pancreatic, colorectal, breast, prostate, ovarian cancer. Previous studies often used bile acids in supraphysiological concentration, sometimes in concentrations 1000 times higher than the highest reported tissue or serum concentrations likely eliciting unspecific effects, a practice that we advocate against in this review. Furthermore, we show that, although bile acids were classically considered as pro-carcinogenic agents (e.g. oesophageal cancer), the dogma that switch, as lower concentrations of bile acids that correspond to their serum or tissue reference concentration possess anticancer activity in a subset of cancers. Differences in the response of cancers to bile acids lie in the differential expression of bile acid receptors between cancers (e.g. FXR vs. TGR5). UDCA, a bile acid that is sold as a generic medication against cholestasis or biliary surge, and its conjugates were identified with almost purely anticancer features suggesting a possibility for drug repurposing. Taken together, bile acids were considered as tumor inducers or tumor promoter molecules; nevertheless, in certain cancers, like breast cancer, bile acids in their reference concentrations may act as tumor suppressors suggesting a Janus-faced nature of bile acids in carcinogenesis.

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Bile acids (BAs) belong to cholesterol-derived sterols. Due to the side chain carboxyl group and hydroxylation of their steroid ring they are more polar than cholesterol. They have an amphipatic character for which they are known as natural detergents. Majority of cholesterol is excreted by bile acids that are prone to enterohepatic circulation between the gallbladder and the liver. Cholesterol absorption in the intestine and cholesterol secretion into the bile both require bile salts, which are, together with enterohepatic circulation of BAs, crucial for balancing the plasma cholesterol level [ 1 ].

BAs are also signaling molecules. They deorphanized the farnesoid X nuclear receptor (FXR) which is now known as a ligand-inducible transcription factor responsive to BAs [ 2 ]. It is important to note that BAs are metabolized in a similar manner as xenobiotics, contributing to the cross-talk between the endogenous and xenobiotic metabolism in the liver through nuclear receptors Pregnane X receptor (PXR), constitutive androstane receptor (CAR) and others [ 3 ]. While their synthesis takes place exclusively in the liver, the homeostasis and excretion involve multiple organs and compartments in the body. After discovering their signaling role, BAs have been considered as pro-carcinogenic molecules [ 4 , 5 , 6 ]. However, recent studies have provided evidence that in certain cancers, BAs can have antineoplastic features (e.g. breast cancer [ 7 , 8 , 9 , 10 , 11 ]). This novel, context-dependent, dualistic finding prompted us to thoroughly assess the involvement of BAs in carcinogenesis and cancer progression.

• Bile acid biosynthesis

The excess of free cholesterol is toxic to cells and needs to be excreted, primarily through conversion to more polar BAs. The introduction of a hydroxyl group in cholesterol reduces the half-life and directs the oxidized molecule to excretion [ 12 ]. BA synthesis is thus the main cholesterol detoxification pathway where multiple cytochrome P450 (CYP) enzymes are involved in the classical or alternative pathways (Fig.  1 ). The two major primary BAs in humans are cholic acid (CA) and chenodeoxycholic acid (CDCA). They are synthesized in the liver and secreted into the gallbladder as glycine or taurine conjugates [ 13 ]. The BA composition in mice substantially differs from the humans which has to be taken into account when using mouse as a model for BA related diseases. The mouse  Cyp2c70  metabolizes CDCA to more hydrophilic primary muricholic acids (MCAs) [ 14 ].

Scheme of the classical and alternative bile acids in humans. Only enzymes of the CYP family are listed while the pathway involves enzymes of other protein families. CA and DCA are conjugated and further metabolized in the intestine

The first enzyme of the classical BA synthesis pathway is cholesterol 7α-hydroxylase (CYP7A1), leading to 7α-cholesterol in a rate-limiting reaction step, followed by several enzymatic conversions. This enzyme is prone to the negative feedback regulation by BAs and FXR [ 2 ]. Sterol 12α-hydroxylase (CYP8B1) lies at the branching point that leads to CA. Sterol 27-hydroxylase (CYP27A1) is needed for both CA and CDCA. In the alternative pathway, cholesterol is first metabolized by CYP27A1 to form 27-hydroxycholesterol that is a substrate for 25-hydroxycholesterol 7α-hydroxylase (CYP7B1) and later other enzymes [ 15 ]. The alternative pathway leads majorly to CDCA. The ratio of CA to CDCA is determined by the expression level of CYP8B1, which transforms a di-hydroxylated BA to tri-hydroxylated BA. The alternative pathway is estimated to account for about 10% of cholesterol conversion [ 16 ]. Of importance, there are major differences in individual BA synthesis genes in mouse and in humans which may be due also to different biological roles of human and mouse BA species (reviewed in [ 15 ]).

Bacterial metabolism of bile acids, production of secondary bile acids

Hepatocytes secrete BAs to the bile canaliculi. By fusing with each other bile canaliculi form bile ducts, which eventually form the hepatic duct that runs to the gallbladder. The gallbladder empties to the duodenum upon feeding and, hence, releases BAs to the gastrointestinal tract. Primary BAs emulsify dietary fats and activate pancreatic lipases in the small bowel. BAs are then reabsorbed through the enterocytes and get to the liver for reuptake and reuse through the portal circulation. This circle is termed the enterohepatic circulation of BAs. A fraction of the reabsorbed BAs enter the systemic circulation (total BA concentration in the serum is < 5 µM in a healthy individual) and exert hormone-like effects [ 7 , 17 , 18 , 19 , 20 ]. The reference concentrations of the serum, tissue and fecal bile acids are in Tables 1 , 2 , 3 .

BAs are very powerful surfactants [ 21 ]; therefore, bacteria, mostly in the large bowel, need to protect themselves against being disintegrated by BAs. For example, lipopolysaccharides serve as membrane components in Gram-negative bacteria to passively ward off external toxins or BAs [ 22 ]. In addition to that, bacteria have a more sophisticated enzymatic system to cope with BAs termed BA conversion [ 23 ].

The hydroxyl groups and the tauryl or glycyl conjugate on BAs are crucial elements of the molecular structure of BAs for their strong surfactant properties. Therefore, the removal, modification or substitution of these molecular elements diminishes the potentially toxic features of primary BAs and renders them largely apolar. The dehydroxylated primary BAs are called secondary BAs and the main site for converting primary BAs to secondary BAs is the large bowel [ 24 ]. Secondary BAs can be resorbed to the portal circulation and are transported to the liver, where, however, hydroxylation and conjugation needs to be restored for reuse. The main secondary BAs in humans are lithocholic acid (LCA), deoxycholic acid (DCA) and to a lesser extent, ursodeoxycholic acid (UDCA) [ 24 , 25 ].

Bile salt hydrolases (BSHs) are responsible for the deconjugation of BAs, namely the removal of glycine or taurine by breaking the C24 N -acyl bond. Glycine and taurine can be fed into the metabolism of bacteria to be used as an energy source [ 23 ]. BSH activity is common among the bacteria inhabiting the small and the large intestines [ 23 ]; both aerobic [ 26 ] and anaerobic bacteria can deconjugate bile salts [ 27 ]. Namely, among the Gram-positive bacteria BSH was identified in Clostridium [ 27 , 28 , 29 , 30 ] , Enterococcus [ 27 , 31 ], Bifidobacterium [ 27 , 32 , 33 ], Lactobacillus [ 34 , 35 ], Streptococcus [ 36 ], Eubacterium [ 37 ] and Listeria , among Gram-negative bacteria in Bacteroides [ 30 , 38 , 39 ], while among archea Methanobrevibacter smithii and Methanosphera stadmanae [ 40 ].

The substituents on the gonane core of BAs can be also modified, the term “secondary BA” typically stands for the removal of 7α or 7β-hydroxyl groups from primary BAs. Clostridiales and Eubacteria were shown to play a major role in dehydroxylation [ 23 , 41 , 42 , 43 , 44 , 45 ], although other genre or species were also implicated (e.g. Bacteroidetes , Escherichia) [ 7 , 38 , 44 , 46 , 47 ]. Although BA deconjugation and dehydroxylation are different processes, they may be linked through regulatory circuits [ 30 ]. Other reactions of BAs involve oxidation, and epimerization that can be linked to intestinal Firmicutes ( Clostridium , Eubacterium , and Ruminococcus ), Bacteroides and Escherichia [ 23 , 36 , 37 , 41 , 42 , 44 , 45 , 48 ]. Bacterial enzymes involved in secondary BA production are assembled in the BA inducible (bai) operon [ 24 ]. Collectively, BA transformation renders secondary BAs hydrophobic and BAs loose their ability to act as detergents or toxins to bacteria. Moreover, these changes are vital in fine-tuning the affinity of BAs to BA receptors.

Interactions between BAs and gut microbiota are bidirectional. Microbiota can transform primary BAs and, hence, modulate the composition of the BA pool [ 49 , 50 ]. Inversely, BAs can influence the composition of the microbiome as well [ 51 , 52 , 53 , 54 , 55 , 56 ] and facilitate bacterial translocation to tissues [ 57 ], further underlining that notion BAs act as potent drivers of the early intestinal microbiota maturation [ 58 ]. Oncobiosis (dysbiosis associated with cancers) [ 59 ] can alter the secondary BA pool that may contribute to carcinogenic effects [ 4 , 5 , 7 , 18 ]. It is of note that several other non-BA bacterial metabolites are known that play role in carcinogenesis [ 60 , 61 , 62 , 63 , 64 ].

• Bile acid transporters

The enterohepatic circulation of BAs depends on BA transporters in the gastrointestinal system. Almost 90% of BAs are involved in circulation due to efficient active transport [ 65 ]. Different uptake and efflux BAs transporters are present in the hepatic and intestinal cells (Fig.  2 ). After BAs are synthesized in the liver they are transported into the bile mainly by the ATP-dependent cassette transporter (BSEP) [ 65 ], but also minor transporters, the multidrug resistance-associated protein 2 (MRP2, ABCC2) and the multidrug resistance protein 1 (MDR1, ABCB1) [ 65 ]. From the intestinal lumen, BAs are uptaken into the intestinal cells by the major apical sodium-dependent bile acid transporter (SLC10A2, ASBT), which transports BAs also across the canalicular membrane in cholangiocytes and renal tubule apical membrane from glomerular filtrate [ 66 ]. BAs are then effluxed into the portal circulation by two Solute Carrier Family members, SLC51A or OSTα and SLC51B or OSTβ. The bile acids are then taken back up into hepatocytes by the major transporter the solute carrier family 10 (SLC10A1, NTCP), [ 65 ].

A scheme of enterohepatic and systemic circulation of bile acids and the transporters in different human cells. Transporters are coloured according to which part of the circulation they belong to. Blue are efflux and influx transporters, which transport BAs in portal circulation. Grey are efflux transporters, which contribute to bile export into bile and faeces. Green are transporters, which are responsible for BA transport into the systemic circulation. Yellow are transporters involved in the efflux of BAs into urine. ASBT/SLC10A2 sodium-dependent bile acid transporter, BSEP/ABCB11 ATP-dependent cassette transporter, MRP2/ABCC2 multidrug resistance-associated protein 2, MRP3/ABCC3 multidrug resistance-associated protein 3, MRP4/ABCC4 multidrug resistance-associated protein 4, OATP1A2/SLCO1A2 Solute Carrier Organic Anion Transporter Family Member 1A2, OATP1B/SLCO1B Solute Carrier Organic Anion Transporter Family, SLC51A/B or OSTα/β Solute Carrier Family members, SLC10A2/ASBT sodium-dependent bile acid transporter

BAs can enter the systemic circulation via export across the hepatic sinusoidal membrane by OSTα/OSTβ, the multidrug resistance-associated protein 3 (MRP3, ABCC3) and the multidrug resistance-associated protein 4 (MRP4, ABCC4) [ 67 ]. The MRP transporters have a role in reducing hepatic BA concentration in cholestatic conditions. MRP3 and MRP4 are also present in cholangiocytes, where they efflux BAs to portal circulation and are part of the cholehepatic shunt together with ASBT [ 66 ]. Several transporters are expressed in the kidney, where they participate in BA elimination via urine (Fig.  2 ) [ 66 , 68 , 69 ]. The Solute Carrier Organic Anion Transporter Family, OATP1B1 or SLCO1B1 and OATP1B3 or SLCO1B3 contribute to the systemic clearance of BAs via liver [ 70 ]. Other cells also express BA transporters and can, therefore, uptake BAs from the systemic circulation [ 68 , 69 , 71 ].

Bile acids as signaling molecules

In addition to their role in digestion, BAs act as signaling molecules. BAs can activate membrane receptors (Fig.  3 ), such as G protein-coupled bile acid receptor 1 (GPBAR1, also known as TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), muscarinic receptors (CHRM2 and CHRM3) and nuclear receptors (NRs), such as farnesoid X receptor (FXR, NR1H4), PXR (NR1H2), vitamin D receptor (VDR, NR1H1), CAR (NR1H3) and liver X receptor (LXR, NR1H2-3). Each BA can interact with more than one receptor. Receptors are differentially activated by BAs. For example, FXR is activated by CDCA > DCA > LCA > CA [ 72 ], while TGR5 is activated by LCA > DCA > CDCA > CA [ 73 , 74 ], respectively. VDR and PXR are mainly activated by LCA. BAs mediate immune responses [ 75 ], gastrointestinal mucosal barrier function, gestation [ 76 ], carcinogenesis [ 11 , 18 , 56 ] and metabolic diseases [ 20 ]. The activation of BA receptors may lead to the induction of signaling pathways involved in the regulation of several physiological functions, such as glucose, lipid and energy metabolism, as well as, in cancers. Below, we review the mode of action of BA receptors and highlight those receptor-mediated functions that have a key role in regulating the behavior of cancer cells.

The subcellular localization of bile acid receptors. TGR5 G protein-coupled bile acid receptor 1, S1PR2 Sphingosine-1-phosphate receptor 2, CHRM2 Muscarinic receptor-2, CHRM3 Muscarinic receptor-3, FXR Farnesoid X receptor, PXR Pregnane X receptor, CAR Constitutive androstane receptor, VDR Vitamin D receptor, SHP Small heterodimer partner

Cell membrane receptors

G protein-coupled bile acid receptor 1 (gpbar1, tgr5).

TGR5 is a member of the G protein-coupled receptor superfamily, highly expressed in the epithelium of the gallbladder [ 77 ], the intestine [ 74 ], the brown adipose tissue and the skeletal muscle [ 20 ], as well as in the brain [ 78 ]. TGR5 is also expressed in human monocytes/macrophages [ 73 ]. TGR5 is not expressed by hepatocytes, while Kupffer cells and liver sinusoidal cells can express the receptor [ 79 ].

Secondary BAs LCA and DCA are the most potent, natural ligands for TGR5, but the receptor also responds to CDCA and CA [ 73 , 74 ] and a set of artificial ligands [ 80 , 81 , 82 , 83 , 84 ] (Table 4 ). Ligand binding to the TGR5 receptor triggers activation of adenylate cyclase leading to the production of cAMP [ 73 , 74 , 85 ] and the downstream activation of extracellular signal-regulated kinase 1/2 (ERK1/2), protein kinase A (PKA), protein kinase B (AKT), mammalian target of rapamycin complex 1 (mTORC1) and Rho kinase [ 86 , 87 , 88 , 89 ]. TGR5 activation leads to metabolic changes characterized by energy expenditure and β-oxidation [ 20 , 90 ]. BA-dependent induction of TGR5 has immunomodulating effects. Most studies point to TGR5-dependent immunosuppression [ 73 , 79 , 91 , 92 , 93 , 94 ] partly due to the suppression of the Toll-Like Receptor 4—Nuclear factor-κB (TLR4–NF‐κB) pathway [ 91 , 93 , 94 ]. In line with that, in a murine model of breast cancer, LCA treatment induced the proportions of tumor-infiltrating lymphocytes through TGR5 [ 7 ].

Sphingosine-1-phosphate receptor 2 (S1PR2)

Conjugated BAs activate S1PR2 [ 95 , 96 , 97 ] that upregulates the expression of sphingosine kinase 2 (SphK2), which in turn enhances the level of sphingosine-1-phosphate in the nucleus. Elevated nuclear sphingosine-1-phosphate inhibits the function of histone deacetylases resulting in the upregulation of genes encoding nuclear receptors and enzymes involved in lipid and glucose metabolism [ 98 ] Similar to TGR5, ligand binding to S1PR2 can activate different downstream signaling pathways, such as ERK, AKT and/or c-Jun N-terminal kinase (JNK1/2) [ 96 , 97 , 99 , 100 ]. Glycochenodeoxycholic acid (GCDCA) can trigger apoptosis in hepatocytes through activating S1PR2 [ 101 ]. S1PR2 is highly expressed in macrophages [ 102 ] and has widespread immunological roles [ 100 , 102 , 103 ].

Muscarinic receptors (CHRM2 and CHRM3)

Taurine conjugated BAs can activate muscarinic receptors, the cholinergic receptor muscarinic 2 and 3 (CHRM2 and CHRM3). CHRMs are overexpressed in colon cancer cells and stimulate cell proliferation and invasion [ 104 , 105 ]. Taurolithocholic acid (TLCA) induces cholangiocarcinoma cell growth via muscarinic acetylcholine receptor and EGFR (epithelial growth factor receptor)/ERK1/2 signaling [ 106 ].

Nuclear receptors

Farnesoid x receptor (fxr, nr1h4).

FXR is a member of the nuclear hormone receptor superfamily. There are two FXR genes, encoding FXRα and FXRβ of which only FXRα is expressed, FXRβ is present as a non-expressed pseudogene in humans. The FXR receptor heterodimerizes with retinoid X receptor (RXR) and binds to FXR response elements (FXREs) within the regulatory regions of its target genes [ 107 ]. BAs are physiological ligands for FXR (with decreasing affinity: CDCA, DCA, LCA, CA) [ 72 ]. FXR is expressed mainly in the liver, intestine, kidney and adrenal glands [ 107 ].

FXRα controls BA synthesis, transport and detoxification. The activation of FXR receptor by BAs reduces the expression of Cyp7a1 and Cyp8b1 , key enzymes of BA biosynthesis pathway. In the liver, FXRα induces the transcription of its target gene encoding small heterodimer partner (SHP, NR5O2), an orphan nuclear hormone receptor (see in detail later) that lacks a DNA binding domain and acts as a transcriptional repressor [ 108 ]. SHP inhibits the expression of Cyp7a1 through the inhibition of the interaction with liver receptor homolog-1 (LRH-1, NR5A2) [ 109 ]. In addition to LRH-1, SHP also prevents the function of hepatocyte nuclear factor-4α (HNF4α), a positive regulator of Cyp7a1 and Cyp8b1 [ 110 ]. In the intestine, FXRα induces the expression of fibroblast growth factor 19 (FGF19) in humans and its mouse homolog fibroblast growth factor 15 (FGF15). The secreted growth factor via portal blood reaches the liver where it binds to its receptor, fibroblast growth factor receptor 4 (FGFR4) and induces JNK and ERK pathways and causes repression of Cyp7a1 , thus reducing BA synthesis [ 111 ]. In addition to Cyp7a1 , Cyp8b1 is also repressed by FXRα via SHP-dependent mechanism involving HNF4α [ 110 ].

FXRα is also a key regulator of BA transport by influencing the expression of BA transporters. FXRα activation suppresses BA reuptake to hepatocytes through repressing the expression of NTCP via SHP dependent mechanism [ 112 ]. At the same time, FXRα facilitates the efflux of BAs from hepatocytes into bile by enhancing the expression of BSEP and into the systemic circulation via OSTα/β transporter [ 113 ]. FXR also upregulates MRP2, which promotes BA secretion into the gallbladder. Finally, FXRα activates the expression of intestinal BA-binding protein (I-BABP) in the ileum which promotes transport of BAs from enterocytes into portal blood [ 114 ] whereas limits enterocyte uptake of BAs by reducing ASBT expression. FXRα increases the expression of enzymes involved in the detoxification of BAs, such as cholesterol 25-hydroxylase or cytochrome P450 family 3 subfamily A4 (CYP3A4) [ 115 ], dehydroepiandrosterone-sulfotransferase (SULT) 2a1 [ 116 ] and uridine 5′-diphosphate-glucuronosyltransferase 2B4 (UGT2B4) [ 117 ]. Many studies have reported the relationship between FXR and inflammation. NF-kB activation suppressed FXR-mediated gene expression, indicating that there is a negative crosstalk between the FXR and NF-kB signaling [ 118 ].

Pregnane X receptor (PXR, NR1I2)

In humans, PXR is mainly expressed in the liver and intestine [ 119 ]. Among BAs, the most potent ligand of PXR is LCA, and the oxidized, 3-keto form of LCA. PXR acts as a xenobiotic sensor and regulates the expression of genes involved in the detoxification and metabolism of BAs [ 120 ]. Upon ligand binding, PXR binds to the promoter of its target gene as a heterodimer with RXR. Activation of PXR induces the uptake of xenobiotics, their modification by phase I enzymes (CYPs, including CYP3A, CYP2B, CYP2C), conjugation by phase II enzymes, such as glutathione S-transferases, UDP-glucuronosyl-transferases (UGTs) and sulfotransferases, and finally elimination by phase III drug transporters including MDR1, MRP2 and organic anion-transporting polypeptide (OATP2) [ 120 ]. The activation of PXR prevents cholesterol gallstone disease by regulating BA biosynthesis and transport [ 121 ] and protects the liver against LCA-induced toxicity [ 122 , 123 , 124 , 125 ]. PXR activation disrupts the interaction between HNF4α and peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PGC-1α, PPARGC1A), which is required for the activation of CYP7A1 gene expression, thus reducing the expression of CYP7A1 and inhibiting the synthesis of BAs [ 126 ]. PXR activation is anti-inflammatory [ 127 , 128 , 129 ]. PXR activation facilitates lipogenesis, suppressing β-oxidation and ketogenesis and gluconeogenesis [ 130 , 131 , 132 ]. Furthermore, PXR through HNF4 and PGC-1α modulates the expression of CYP7A1 [ 133 ].

Constitutive androstane receptor (CAR, NR1I3)

CAR is the closest relative to the PXR and is expressed primarily in the liver. First studies identified that CAR has constitutive transcriptional activity in the absence of its ligand [ 134 ]. Later, it was reported that the constitutive transcriptional activity of CAR is reversed by androstane metabolites, which are inverse agonists [ 135 ]. CAR can be activated by direct ligand binding and indirect activation [ 136 ]. In the absence of ligand binding, CAR forms a heterodimer with RXR and transactivates its target genes [ 137 ]. CAR recruits coactivators in the nucleus, such as steroid receptor coactivator 1 (SRC-1, NC0A1) and PGC-1 [ 138 ]. Similar to PXR, CAR controls the expression of drug-metabolizing enzymes and transporters, thereby supporting the detoxification of xenobiotics [ 120 , 139 ]. In contrast to PXR, it remains unclear whether BAs can function as natural ligands for CAR; nevertheless, there are reports underscoring the involvement of CAR in BA signaling [ 11 ].

Vitamin D receptor (VDR, NR1I1)

In humans, VDR is highly expressed in the kidney, intestine, bone as well as in hepatocytes but expressed at low levels in other tissues [ 140 , 141 , 142 ]. LCA is a potent endogenous VDR ligand [ 143 , 144 ]; hence, VDR can act as an intestinal BA sensor. VDR activation induces expression of CYP3A that metabolizes LCA [ 143 , 145 ]. In addition, VDR induces the expression of SULT2A1 , MRP3 and ASBT to stimulate BA sulfonation, excretion and transport [ 146 , 147 , 148 ]. The activated VDR plays a role in the inhibition of BA synthesis via suppression of CYP7A1 , thus protecting liver cells during cholestasis [ 140 ].

VDR can function as a nuclear receptor and a membrane-bounded receptor. Upon ligand binding, VDR translocates into the nucleus, where it binds to DNA response elements as a heterodimer with RXR to mediate gene transcription. Plasma membrane-associated VDR receptor activates several signaling cascades to inhibit CYP7A1 transcription [ 142 , 149 ]. It has been shown that the activation of membrane VDR signaling by LCA in the liver activates MEK1/2ERK1/2 pathway, which stimulates nuclear VDR/RXRα heterodimer recruitment of corepressors to inhibit CYP7A1 gene transcription [ 150 ]. In biliary epithelial cells, bile salts (CDCA, UDCA) stimulate the expression of cathelicidin, an antimicrobial peptide, via VDR and FXR to control innate immunity [ 151 ]. The possible role of VDR in regulating immunity and the role of VDR in different cancer cells and diseases is reviewed in detail elsewhere [ 152 ].

Liver X receptor (LXR, NR1H2-3)

LXRs are activated by naturally occurring cholesterol metabolites such as oxysterols and bind to DNA as heterodimers with the RXR [ 153 ]. LXRα (NR1H3) and LXRβ (NR1H2) share a high structural homology [ 154 ]. LXRβ is ubiquitously expressed, while LXRα is primarily expressed in the liver, the adipose tissue, the intestine and macrophages. Upon ligand activation LXRs regulate gene expression via binding to LXR response elements in the promoter regions of the target genes. LXRα promotes the conversion of cholesterol into BAs through the induction of CYP7A1 expression in the liver. LXRs enhance the efflux of cholesterol from cells [ 155 ] and have an anti-inflammatory response in the adipose tissue and macrophages [ 156 ]. Hyodeoxycholic acid (HDCA), a naturally occurring secondary BA generated by bacterial C-6 hydroxylation of LCA, is a weak LXRα agonist [ 157 ].

Small heterodimer partner (SHP, NR5O2)

SHP is a unique nuclear receptor that contains a ligand-binding domain but lacks the conserved DNA-binding domain. SHP acts as a transcriptional corepressor regulating different metabolic processes, including lipid, glucose, energy homeostasis and BA synthesis via interaction with multiple transcription factors and nuclear receptors (reviewed in [ 158 ]). BAs or FGF19 signaling enhances posttranslational modifications of SHP, which modulates the regulatory function of SHP protein [ 159 , 160 ]. SHP acts as an inhibitory regulator in Hedgehog/Gli signaling pathway [ 161 ].

Effects of bile acids in cancers

The role of BAs was implicated in a wide variety of neoplasias (Fig.  4 , Tables 5 , 6 , 7 ). When assessing the effects of BAs, one has to keep in mind that the concentrations applied in the experiments need to correspond to the reference concentrations in serum or the compartment in question (e.g. parts of the gastrointestinal tract). However, several reports are using substantially higher concentrations than the reference. These studies need to be considered as ones using “therapeutic” concentrations. In the forthcoming chapters, we will review those neoplasias where BAs were implicated in pathogenesis.

Different roles of bile acids and bile acids receptors in a wide variety of cancers. Some BAs have opposite effects, which depend on the cell line, BA concentration and other treatment conditions. The crossed circle symbol marks the tumor suppressor effects and the arrow marks the tumor promoter effects. CA Cholic acid, CAR Constititive androstane receptor, CDCA Chenodeoxycholic acid, CHRM2/M3 Muscarinic receptor 2 and 3, DC Deoxycholate, DCA Deoxycholic acid, FXR Farnesoid X receptor, GCDA Glycochenodeoxycholate acid, GCDC Glycochenodeoxycholate, GDC Glycodeoxycholate, GDCA Glycodeoxycholic acid, GLCA Glycolithocholic acid, GUDCA Glycoursodeoxycholic acid, LCA Lithocholic acid, PXR Pregnane X receptor, S1PR2 Sphingosine-1-phosphate receptor 2, SHP Small heterodimer partner, TCA Taurocholic acid, TCDC Taurochenodeoxycholate, TCDCA Taurochenodeoxycholic acid, TDC Taurodeoxycholate, TDCA Taurodeoxycholic acid, TGR5/GPBAR1 G protein- coupled bile acid receptor 1, TLC Taurolithocholate, TLCA Taurolithocholic acid, TUDCA Tauroursodeoxycholic acid, UDCA Ursodeoxycholic acid, VDR Vitamin D receptor

• Oesophageal carcinoma

The development of Barrett’s esophagus (BE) and its progression to oesophageal adenocarcinoma (EAC) are linked to gastroesophageal reflux disease (GERD). Conjugated BAs, mainly taurocholic acid (TCA) and glycocholic acid (GCA) are the main BA constituents in GERD refluxate [ 162 ]. Conjugated BA levels in the refluxate from patients with advanced BE or EAC are significantly higher than from patients with benign BE [ 163 ]. Conjugated BAs, as TCA or taurodeoxycholic acid (TDCA), promote EAC progression [ 164 , 165 ] (Table 7 ). Unconjugated BAs, including DCA and CDCA, induce oxidative stress, DNA damage and inflammation contributing to EAC carcinogenesis, while UDCA protects against DCA-induced injury (Tables 5 and 7 ).

Apparently, numerous BA receptors as TGR5, S1PR2, FXR and VDR are activated in EAC cells in response to BAs in the refluxate [ 164 , 165 , 166 , 167 ]. In good agreement with that, the inhibition of the FXR receptor suppresses tumor cell viability in vitro and reduced tumor formation in nude mouse xenografts [ 168 ]. Furthermore, TGR5 is highly expressed in the EAC and precancerous lesions and is associated with worse overall survival [ 169 ] suggesting that these observations can be translated to the human situation.

Acidic bile acids bring about oxidative stress, TDCA can induce NADPH Oxidase 5 (NOX5) through TGR5 [ 164 ]. Furthermore, bile acids can induce inflammation through FXR activation [ 170 ] and the EGFR–STAT3 (signal transducer and activator of transcription 3)—Apurinic/Apyrimidinic Endodeoxyribonuclease 1 (APE1) pathway [ 171 ]. Acidic bile salts can also induce epithelial–mesenchymal transition (EMT) through vascular endothelial growth factor (VEGF) signaling in Barrett's cells [ 172 ]. Interestingly, the activation of the EGFR-DNA-PKs (DNA-dependent protein kinase) pathway by insulin-like growth factor binding protein 2 (IGFBP2) protects EAC cells against acidic bile salt-induced DNA damage [ 173 ].

• Gastric cancer

Carcinogenesis in gastric cancer is a sequential process that includes chronic superficial gastritis, intestinal metaplasia (IM), atrophic gastritis, intramucosal carcinoma, dysplasia and invasive neoplasia [ 174 ]. IM is considered a risk factor for gastric tumorigenesis. The concentrations of BAs in gastric juice positively correlate with the degree of intestinal metaplasia [ 175 ] and BAs serve a critical multipronged role in the induction of intestinal metaplasia. BAs can enhance caudal-related homeobox family 2 (CDX2) and mucin 2 (MUC2) expression via FXR/NF-κB signaling [ 176 , 177 ] and cyclooxygenase-2 (COX-2) expression via induction of SHP [ 178 ], all promoting gastric intestinal metaplasia. Acidic bile salts can induce telomerase activity in a c-Myc-dependent fashion [ 179 , 180 ], while DCA can induce the metaplastic phenotype of gastric cancer cells [ 181 ] (see Tables 6 and 7 ). TGR5 is a key factor in BA-induced gastric metaplasia via HNF4α [ 181 ], EGFR and mitogen-activated protein kinase (MAPK) [ 182 ] activation and promotes EMT in gastric carcinoma cells [ 183 ]. TGR5 is overexpressed in gastrointestinal adenocarcinomas, and moderate to strong TGR5 staining is associated with decreased patient survival [ 184 ]. Nevertheless, there anticarcinogenic effects of bile acids in gastric cancer, as UDCA (Table 5 ) or DCA in supraphysiological concentrations [ 185 , 186 ] or 23(S)-mCDCA [ 187 ].

Hepatocellular carcinoma (HCC)

Several studies have shown that more hydrophobic BAs as LCA, DCA and CDCA, are the main promoters of liver cancer and can contribute to the development of HCC (see in Table 7 ) [ 188 , 189 , 190 , 191 , 192 ]. Nevertheless, CDCA (> 100 µM) [ 193 , 194 ], UDCA and Tauroursodeoxycholic acid (TUDCA) inhibit HCC cell growth and induce apoptosis [ 195 , 196 , 197 , 198 , 199 ] (see in Tables 5 and 6 ). Deregulation of BA homeostasis marked by the expression of hepatic BA transporters (BSEP, OSTα/β, MRP2, MDR2-3, NTCP) is diminished leading to increased hepatic BA sequestration and inflammation and reduced FXR signaling [ 200 , 201 , 202 , 203 ] in liver cirrhosis and nonalcoholic steatohepatitis that are risk factors for the development of HCC. In good agreement with that, metabolomics identified long-term elevated serum BAs in HCC patients [ 204 ] and children (< 5 years of age) with bile salt export pump deficiency developed HCC [ 205 ].

FXR activity is a major inhibitor of HCC carcinogenesis. Whole-body FXR-deficient mice spontaneously develop liver tumors [ 206 , 207 ] in which the activation of the Wnt/β-catenin signaling pathway and oxidative stress were identified as the major drivers [ 208 , 209 , 210 ]. Nevertheless, liver-specific FXR deficiency in mice does not induce spontaneous liver tumorigenesis, but may only serve as a tumor initiator [ 211 ]. Due to their amphipathic nature, BAs can disrupt the plasma membrane and activate protein kinase C (PKC) and phospholipase A2 (PLA2) inducing the p38-MAPK-p53-NFκB pathway [ 212 , 213 ]. Inflammation can suppress FXR activity that contributes to bile acid accumulation and carcinogenesis [ 185 , 193 , 194 , 214 ].

Interestingly, senescence-associated secretory phenotype has crucial role in promoting obesity-associated HCC development in mice. Administration of high-fat diet to mice induces alterations in the gut microbiota and increases the levels of DCA. Increased DCA level promotes SASP phenotype in hepatic stellate cells (HSCs), which in turn secretes various tumor-promoting factors in the liver, thus facilitating HCC development in mice exposed to chemical carcinogen [ 6 ]. SHP has a pleiotropic role in HCC, regulates cell proliferation [ 215 ], apoptosis [ 216 ], epigenetic changes [ 217 ] and inflammation [ 200 , 218 ], which are associated with the antitumor role of SHP in the development of liver cancer.

• Pancreatic adenocarcinoma

BAs are involved in the induction and development of pancreatic adenocarcinoma at multiple stages. Gallstone formation can block bile flow and, therefore, can induce and sustain pancreatitis [ 219 ], a risk factor for pancreatic adenocarcinoma [ 220 , 221 , 222 ]. In fact, several BA species showed a drastic increase in pancreatic adenocarcinoma patients [ 223 ]. Treatment of pre-malignant pancreas ductal cells with bile induced carcinogenic transformation [ 224 , 225 ]. In pancreatic adenocarcinoma cells BAs decrease susceptibility to apoptosis, boost cell cycle progression, the expression of inflammatory mediators and cellular movement, and, in high concentrations, may perturb biomembranes (Table 7 ) [ 220 , 226 ]. UDCA, similar to its previously discussed beneficial properties, prevents EMT in pancreatic adenocarcinoma cell lines and, therefore, has antineoplastic properties (Table 5 ) [ 227 ].

Colorectal carcinoma (CRC)

The western diet has tumor promoting activity associated with elevated concentrations of colonic BA (mainly LCA and DCA) and increased fecal BA levels, as detected in samples from CRC patients [ 228 ]. In animals, a high-fat diet stimulates bile discharge and results in elevated BA levels in the colon [ 229 ]. Moreover, cholecystectomy, through prolonging BA exposure of the intestinal mucosa, has been suggested as a risk factor for the development of CRC [ 230 ].

BAs induce genetic instability marked by genomic instability and DNA damage via oxidative stress, defects in mitotic checkpoints, cell cycle arrest, improper chromosome alignment and multipolar division [ 231 , 232 ]. Genomic instability caused by BAs is coupled with apoptosis resistance due to the degradation of p53 and the inhibition of caspase-3 activity [ 233 ]. Furthermore, secondary BAs perturb cell membranes and modulate signaling cascades [ 234 , 235 ]. These all lead to colonic cell hyperproliferation, survival and invasion [ 236 , 237 ].

The disruptive effect of BAs on colon epithelium evokes a compensatory cell renewal mechanism by inducing colonic epithelial cells to become cancer stem cells (CSCs) through β-catenin signaling (Table 7 ) [ 238 ]. In the CRC rodent model, both LCA and DCA have tumor promoter role on colonic crypt cells in the early stages of colon carcinogenesis [ 239 ]; however, it is important to note that BAs are suggested as tumor promoters, but not as mutagenic agents, since they can not induce tumor formation without a carcinogen/mutagen or a genetic alteration [ 240 , 241 ]. It should be noted that DCA in low concentrations (0.05–0.3 mM) inhibit colonic cell proliferation via cell cycle block and apoptosis pathways (Table 6 ) [ 242 ].

UDCA can reduce the concentration of toxic BA in stool and blood [ 243 ] and has shown to protect against CRC by inhibiting CSC and CRC cell formation and proliferation [ 244 , 245 ], oncogenic signaling pathways [ 246 ], as well as, inducing tumor surveillance [ 247 ] (Table 5 ). Moreover, UDCA can reduces CRC recurrence [ 248 ], as well as the risk to develop CRC in patients with pre-cancerous conditions, as colitis [ 249 ] or primary biliary cirrhosis [ 250 ].

Sustained inflammation was implicated in the pathogenesis of colorectal cancer due to barrier breach, and bacterial translocation leading to inflammation and neoplastic transformation of colonic epithelial cells [ 251 , 252 , 253 ]. TGR5 activation by UDCA and LCA may also exert anti-inflammatory responses through TLR4 activation or by reducing pro-inflammatory cytokine production in the colon that can decrease the frequency of developing CRC [ 254 ]. BAs can change the gut microbial community [ 255 , 256 ], suggesting that BAs may also interfere with bacterial translocation.

• Breast cancer

The BAs in the breast are of gut origin [ 257 , 258 ]. Hepatic production of BA is reduced in breast cancer patients as marked by decreasing levels of serum and fecal BAs [ 7 , 259 ]. Furthermore, bacterial conversion of BAs to secondary BAs is also suppressed, which is the most dominant in in situ and stage I patients [ 7 ]. The serum bile acid composition of breast cancer and benign breast disease patients is different; specifically, breast cancer patients had higher serum chenodeoxycholic acid levels and lower dihydroxy tauro-conjugated BA (Tdi-1) and sulfated dihydroxy glyco-conjugated bile acids (Gdi-S-1) [ 260 ]. Total fecal bile acid levels are lower in breast cancer patients as compared to controls [ 259 ]. LCA concentrations in the breast can be higher than the serum levels [ 261 ] (Table 6 ). Reports showed increased DCA levels in the serum [ 262 ] and the breast cyst fluid [ 263 ] of breast cancer patients.

LCA is an inhibitor of breast cancer cell proliferation (Table 6 ) [ 7 , 258 , 264 ]. However, the reports on DCA and UDCA are contradictory [ 7 , 258 , 262 , 263 , 264 ] in physiological concentrations, LCA tunes cancer cell metabolism towards a more oxidative state (through AMP-activated protein kinase (AMPK), PGC-1β and NRF1/NFE2L1) and induces mild oxidative stress through reducing NRF2 (nuclear factor erythroid 2-related factor 2, NFE2L2) expression and inducing Inducible nitric oxide synthase (iNOS) that reverts EMT, reduces VEGF expression, induces antitumor immunity and changes to cancer metabolism that culminates in reduced metastasis formation [ 7 , 11 ]. In supraphysiological concentrations (> 1 µM) LCA inhibits fatty acid biosynthesis [ 10 ] and induces cell death [ 8 , 9 , 10 , 265 , 266 ]. LCA does not exert antiproliferative effects in its tissue reference concentrations on non-transformed primary fibroblasts [ 7 ]. LCA exerts its antineoplastic effects through the TGR5 [ 7 ] (Table 6 ).

CDCA in supraphysiological concentrations induces MDRs through FXR [ 265 ] and modulates estrogen and progesterone receptor-mediated gene transcription [ 267 ]. Furthermore, CDCA inhibits tamoxifen-resistant breast cancer cell proliferation through the activation of the FXR receptor [ 268 ] (Table 6 ). In contrast to that, a report by Journe and colleagues [ 269 ] showed that FXR activation has a positive correlation with estrogen receptor expression and luminal characteristics, as well as supported cancer cell proliferation.

• Prostate cancer

Among the BAs LCA, UDCA and CDCA exerted antiproliferative effects in prostate cancer. Activation of FXR by CDCA inhibits proliferation of prostate cancer cells, reduces lipid anabolism via inhibiting Sterol Regulatory Element Binding Transcription Factor 1 (SREBF1) [ 270 ] and induces the expression of the tumor suppressor phosphatase and tensin homolog (PTEN) [ 271 ] (Table 6 ). Interestingly, FXR signaling also controls androgen metabolism in prostate cancer cells, its activation reduces the expression of UDP-glucuronosyltransferase (UGT) 2B15 and UGT2B17 within cells and causes a reduction of androgen glucuronidation [ 272 ]. Similar to CDCA, LCA has antiproliferative effects in prostate cancer and induces apoptosis, endoplasmic reticulum stress, autophagy and mitochondrial dysfunction [ 9 , 273 ] (see Table 6 ). UDCA induces death receptor-mediated apoptosis in human prostate cancer cells [ 274 ] (Table 5 ).

• Ovarian cancer

In the serum of ovarian cancer patients, 3b-hydroxy-5-cholenoic acid, GUDCA, DCA and TCDCA levels decreased [ 275 , 276 ]; importantly, taurochenodeoxycholic acid levels decreased in early-stage epithelial ovarian cancer [ 276 ]. Zhou and colleagues have shown that sulfolithocholylglycine and TCA showed changes in the serum of ovarian cancer patients [ 277 ]. Changes to the BA pool are so characteristic that Guan and colleagues suggested [ 278 ] a set of 12 BAs, including glycolithocholic acid, to be used as markers to separate healthy controls from ovarian cancer patients.

The available studies assessed the effects of BAs at supraphysiological concentrations. These concentrations of BAs are cytotoxic and induce apoptosis likely due to changes to membrane damage [ 279 , 280 ] that is unlikely at physiological concentrations of BAs [ 7 ]. DCA can modulate the expression of breast cancer type 1 susceptibility protein (BRCA1) and the estrogen receptor and, through these, can control drug sensitivity of ovarian cancer cells (Table 6 ) [ 281 ]. Furthermore, cholylglycinate interferes with the transport of cisplatin [ 282 ] and TCDC sensitizes ovarian carcinoma cells to doxorubicin and Mitomycin [ 280 ].

LXR [ 283 , 284 , 285 ], PXR [ 286 ], VDR [ 287 , 288 , 289 , 290 , 291 , 292 , 293 , 294 , 295 , 296 ] or CAR [ 297 , 298 ] activation was shown to exert protective features against ovarian cancer, similar to BA-elicited effects suggesting that BAs may have a more profound role in protecting against ovarian cancer. These protective effects involved the suppression of proliferation [ 283 , 284 , 286 ], invasion [ 291 ], EMT [ 288 ], de novo fatty acid biosynthesis [ 295 ], the proportions of the cancer stem cell population [ 289 ], and the improvement of the efficacy of chemotherapy [ 285 , 297 , 298 ] culminating in better patient survival [ 292 , 293 ]. Conflicting with these observation on report provided evidence that under certain conditions PXR may support proliferation [ 299 ]. BAs can influence the expression and the activity of multiple PARP enzymes [ 300 ]; therefore, it is likely that BAs could modulate the efficacy of PARP inhibition that is a novel modality in the chemotherapy of ovarian cancer.

Conclusions

Primary and secondary BAs are long-standing players in carcinogenesis. Although these molecules were considered as initiators of neoplasias, recent advances have shown that the pro- or anticarcinogenic activity of BAs varies among neoplasias [ 301 ], most probably due to differences in the expression of BA receptors, transporters and cell-specific differences in the outcome of receptor activation. Key pathways activated in neoplasias by BAs are regulated by nuclear receptors, FXR, CAR, SHP, PXR, LXR and VDR and other membrane receptors such as S1PR2, TGR5, CHRM2 and CHRM3. They activate numerous downstream signaling pathways such as EGFR, STAT3, MAPK, HNF4α, NF-κB, TLR4, SOCS3 and β-catenin just to name some. Furthermore, BAs regulate all aspects of tumor development and progression, the EMT, invasion, metabolism, apoptosis, proliferation, senescence, immune environment and response to chemotherapy.

The effect of BAs on neoplasias also depends on the concentrations used in the studies. While in certain models BAs in low concentration have anti-cancer effects, in superphysiological concentrations BAs have pro-cancer effects. This phenomenon is related to their amphipathic structure and the activation of additional off-target pathways not tiggered at physiological concentration. At high concentrations, BAs may perturb membranes and activate signaling pathways that sense disturbance of membranes, such as PLA2 and PKC. At high concentrations, they are also toxic and activate the detoxifying pathways, which regulate the activity of transporters of steroid hormones and chemotherapeutics. Therefore, we would urge the community to carry out studies where the concentrations of BAs correspond to the reference concentrations established for the tissue or, as a proxy, to the serum reference concentrations. As a continuation of that, in the case of UDCA the therapeutic serum concentrations can also be used as a guide. These data are summarized in Table 1 . Such studies would be invaluable to understand the (patho)physiological roles of BAs and would give a good frame for the therapeutic applicability.

Along the same lines, it is apparent that BAs can be considered as possible treatment options in certain cancers. Foremost, UDCA, that is a therapeutically available drug, has beneficial effects in multiple neoplasias (e.g. [ 227 , 248 , 302 ], Table 5 ) pointing towards the possibility for repurposing UDCA. The picture for other BAs is hazier due to frequent contradictions making it hard to outline applicability. However, before the application of BAs in neoplasias we would need to decipher the cross-talk between BAs and drug metabolism, the effect on drug efficacy and drug availability, and discover the possible adverse effects of BAs, that is currently largely missing. Moreover, it is tempting to consider the manipulation of the intestinal microbiome to affect the levels of selected secondary bile acids in humans . Finally, the modulators of BA receptors should be considered as therapeutic options as well. Given the emerging evidence on the potential anti-cancer effects of BAs, further studies are vital in order to develop novel therapeutic strategies using BAs.

Search strategy and selection criteria

References to this review were identified through the prior knowledge of the authors that was complemented by systematic search of PubMed by using the combinations “Prostate cancer AND (bile acid)”, “Gastric cancer AND (bile acid)”, “Hepatocellular carcinoma AND (bile acid)”, “Oesophageal cancer AND (bile acid)”, “(bile acid) receptors AND cancer”, “(bile acid) receptors AND prostate cancer”, “(bile acid) receptors AND gastric cancer”, “(bile acid) receptors AND hepatocellular carcinoma”, “(bile acid) receptors AND oesophageal cancer”, "(bile acid) AND ABC AND transporter", "(bile acid) AND SLC AND transporter", "(bile acid) AND SLCO AND transporter", "(bile acid) AND transport AND review", “Farnesoid X receptor (FXR) AND the cancer types assessed in the study”, “Pregnane X receptor (PXR) AND the cancer types assessed in the study”, “Constitutive androstane receptor (CAR) AND the cancer types assessed in the study”, “Vitamin D receptor (VDR) AND the cancer types assessed in the study” “Liver X receptor (LXR) AND the cancer types assessed in the study”, “Small heterodimer partner (SHP) AND the cancer types assessed in the study”. Articles published in English were included with no restriction on publication date. All references were checked at Pub Peer, two papers were flagged ([ 215 ] and [ 156 ]), but when reviewing the reports we decided that the issues raised do not impact on the main message and kept the references.

Availability of supporting data

Not applicable.

Abbreviations

Serine/threonine kinase 1

AMP-activated protein kinase

Activator protein-1

Apurinic/apyrimidinic endodeoxyribonuclease 1

Autophagy related 5

Bile acid inducible operon

Bcl-2-associated X protein

B-cell lymphoma 2

Barrett’s esophagus

Coiled-coil myosin-like BCL2-interacting protein

Baculoviral IAP repeat-containing protein 7

ATP-dependent cassette transporter

Bile salt hydrolases

Breast cancer type 1 susceptibility protein

Cholic acid

Cyclic adenosine monophosphate

Constitutive androstane receptor

Chenodeoxycholic acid

Caudal type homeobox 1/2

CCAAT/enhancer-binding protein alpha

Muscarinic receptor 2/3

Myc-related translation/localization regulatory factor

Cyclooxygenase-2

• Colorectal carcinoma

CAMP response element-binding protein

Cancer stem cells

Cytochrome P450

Cholesterol 7α-hydroxylase

25-Hydroxycholesterol 7α-hydroxylase

Sterol 12α-hydroxylase

Sterol 27-hydroxylase

Cytochrome P450 family 3 subfamily

Deoxycholate

Deoxycholic acid

Deleted in Liver Cancer 1

DNA-dependent protein kinase

Death receptor 5

Oesophageal adenocarcinoma

Epidermal growth factor

Epithelial growth factor receptor

• Epithelial–mesenchymal transition

EPH Receptor A2

Estrogen receptor

Extracellular signal-regulated kinase

Focal adhesion kinase

Fas Cell Surface Death Receptor

Fibroblast growth factor 19

Fibroblast growth factor 15

Fibroblast growth factor receptor 4

Fetal liver kinase 1/Kinase Insert Domain receptor

Farnesoid X receptor

FXR response elements

Growth arrest- and DNA damage-inducible gene 153

Gallbladder cancer

Gastroesophageal reflux disease

Glycocholic acid

Glycochenodeoxycholic acid

Glycochenodeoxycholate acid

Glycochenodeoxycholate

Glycodeoxycholate

Glycodeoxycholic acid

Glycolithocholic acid

G-protein-coupled bile acid receptor/Takeda-G-protein-receptor-5

Glycoursodeoxycholic acid

• Hepatocellular carcinoma

Hyodeoxycholic acid

Human epidermal growth factor receptor 2

Hepatocyte nuclear factor-4α

Hepatic stellate cells

Intestinal BA-binding protein

Insulin-like growth factor binding protein 2

Inhibitor Of Nuclear Factor Kappa B Kinase Subunit Beta

Interleukin 1

Interleukin 6

Interleukin 8

Inducible nitric oxide synthase

Janus kinase 2

C-Jun N-terminal kinase

Jun Proto-Oncogene AP-1 Transcription Factor Subunit

Kruppel Like Factor 4

Ligand-binding domain

Lithocholic acid

Lithocholyltaurine

Limit of detection

Liver receptor homolog-1

Liver X receptor

Muscarinic acetylcholine receptor

Mitogen-activated protein kinase

Muricholic acid

Induced myeloid leukemia cell differentiation protein

Mouse double minute 2

Double Minute 4

Multidrug resistance protein 1

Matrix metalloproteinase 2

Matrix metalloproteinase 9

Multidrug resistance-associated protein 2

Multidrug resistance-associated protein 3

Multidrug resistance-associated protein 4

Nuclear mitogen- and stress-activated protein kinase 1

Mammalian target of rapamycin

Mammalian target of rapamycin complex 1

MutY DNA Glycosylase

Myc proto-oncogene protein

Neuroblastoma

N-Myc downstream regulated gene 2

Not detected

Nuclear factor κappa-light-chain-enhancer of activated B cells

NADPH Oxidase 5

Nuclear receptor

Nuclear factor erythroid 2-related factor 2

Nuclear receptor subfamily 4 group A member 1

Non-small cell lung cancer

Sodium/taurocholate cotransporting polypeptide

Solute carrier organic anion transporter family member 1A2

Solute carrier organic anion transporter family

Organic anion-transporting polypeptide

Octamer-binding transcription factor

8-Oxoguanine DNA glycosylase

Peroxisome proliferator-activated receptor gamma coactivator 1 alpha

Prostaglandin E2

Phosphatidylinositol 3-kinase

Protein kinase A

Protein kinase C

Phospholipase A2

Peroxiredoxin II

Pregnane X receptor

Phosphatase and tensin homolog

P38 MAP kinase

Rac family small GTPase 1

Proto-oncogene, serine/threonine kinase

Ras homolog family member A

Reactive nitrogen species

Reactive oxygen species

Retinoid X receptor

Sphingosine-1-phosphate receptor 2

Small heterodimer partner

Solute carrier family 10

Sodium-dependent bile acid transporter

Solute carrier family members

Steroid receptor coactivator 1

Second mitochondria-derived activator of caspase

Suppressor of cytokine signaling 3

Sphingosine kinase 2

Sterol regulatory element-binding factor

Signal transducer and activator of transcription 3

Sulfotransferase

Taurocholic acid

Taurochenodeoxycholate

Taurochenodeoxycholic acid

Taurodeoxycholate

Taurodeoxycholic acid

Telomerase Reverse Transcriptase

Transforming growth factor β-1

Taurolithocholate

Taurolithocholic acid

Toll-Like Receptor 4

TSC Complex Subunit 1

Tauroursodeoxycholic acid

Uncoupling protein-2

Ursodeoxycholic acid

UDP-glucuronosyl-transferase

Uridine 5′-diphosphate-glucuronosyltransferase 2B4

Urokinase-type plasminogen activator receptor

Vitamin D receptor

Vascular endothelial growth factor

Wingless-type MMTV integration site family

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Acknowledgements

Open access funding provided by University of Debrecen. Our work was supported by grants from the NKFIH (K123975, FK128387, DE-ÚNKP-21–5-DE-462, ÚNKP-21–3-I-DE-105). Edit Mikó was supported by the Bolyai fellowship of the Hungarian Academy of Sciences. “Project no. TKP2021-EGA-19 and TKP2021-EGA-20 has been implemented with the support provided from the National Research, Development and Innovation Fund of Hungary, financed under the TKP2021-EGA funding scheme.” PB was supported by a grant from the Hungarian Academy of Sciences (POST-COVID2021-33). Our work was supported by the Slovenian Research Agency programme grant P1-0390.

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Režen, T., Rozman, D., Kovács, T. et al. The role of bile acids in carcinogenesis. Cell. Mol. Life Sci. 79 , 243 (2022). https://doi.org/10.1007/s00018-022-04278-2

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REVIEW article

The anticancer activity of bile acids in drug discovery and development.

• 1 Department of Biliary-Pancreatic Surgery, Renji Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
• 2 Shanghai Key Laboratory of Biliary Tract Disease Research, Shanghai, China
• 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai, China
• 4 Shanghai Research Center of Biliary Tract Disease, Shanghai, China

Bile acids (BAs) constitute essential components of cholesterol metabolites that are synthesized in the liver, stored in the gallbladder, and excreted into the intestine through the biliary system. They play a crucial role in nutrient absorption, lipid and glucose regulation, and the maintenance of metabolic homeostasis. In additional, BAs have demonstrated the ability to attenuate disease progression such as diabetes, metabolic disorders, heart disease, and respiratory ailments. Intriguingly, recent research has offered exciting evidence to unveil their potential antitumor properties against various cancer cell types including tamoxifen-resistant breast cancer, oral squamous cell carcinoma, cholangiocarcinoma, gastric cancer, colon cancer, hepatocellular carcinoma, prostate cancer, gallbladder cancer, neuroblastoma, and others. Up to date, multiple laboratories have synthesized novel BA derivatives to develop potential drug candidates. These derivatives have exhibited the capacity to induce cell death in individual cancer cell types and display promising anti-tumor activities. This review extensively elucidates the anticancer activity of natural BAs and synthetic derivatives in cancer cells, their associated signaling pathways, and therapeutic strategies. Understanding of BAs and their derivatives activities and action mechanisms will evidently assist anticancer drug discovery and devise novel treatment.

1 Introduction

Bile acids (BAs) are physiological metabolites that are synthesized in the liver, stored in the gallbladder, and excreted into the intestine through the biliary system ( Chiang and Ferrell, 2019 ). BAs participate in the nutrient absorption and secretion, and regulate lipids and glucose metabolism, thus maintaining metabolic homeostasis ( Collins et al., 2023 ). Although BAs regulate intestinal flora growth, the intestinal flora can in turn metabolize BAs and control their composition and storage in the enterohepatic circulation through an enterohepatic circulation. A number of factors including fasting and ingesting specific nutrients can regulate BA synthesis, intestinal flora composition, and blood circulation hormones to keep systemic metabolic homeostasis and prevent from BA-associated metabolic diseases. Activation of BA receptor signaling offers protection to the gastrointestinal tract against inflammation and damage. Furthermore, various factors, including gene mutations for the BA synthesis and transport, high-fat diets, medications, and circadian rhythm disturbances, are found to mediate the pathologies of multiple diseases that involve cholestatic liver disease, inflammatory bowel disease, diabetes, obesity, tumors, and related metabolic disorders ( Li and Chiang, 2014 ; Fiorucci et al., 2021 ; Fu et al., 2021 ; Perino et al., 2021 ; Yang et al., 2021 ; Shi et al., 2023 ). In recent years, several researches have demonstrated that BAs have antitumor properties in various cancer cell types, such as tamoxifen-resistant breast cancer ( Luu et al., 2018 ; Kovács et al., 2019 ), oral squamous cell carcinoma ( Talebian et al., 2020 ), cholangiocarcinoma ( Lee et al., 2022 ), gastric cancer ( Zhang et al., 2022 ), colon cancer ( Kim E. K. et al., 2017 ), hepatocellular carcinoma ( Fan et al., 2023 ), prostate cancer ( Lee et al., 2017 ), gallbladder cancer ( Lin et al., 2020 ; Li et al., 2022 ), neuroblastoma ( Trah et al., 2020 ) etc., by inhibiting cancer cell proliferation and migration. In addition, new BA derivatives have been synthesized in several laboratories to investigate their anticancer properties. These derivatives were demonstrated to trigger cell death in cancer cells and exhibit anti-tumor properties ( Katona et al., 2009 ; Sreekanth et al., 2013 ; Tang et al., 2018 ; Markov et al., 2019 ; Agarwal et al., 2021 ; Melloni et al., 2022 ). This review discusses the anticancer activity of natural BAs and synthetic derivatives in cancer cells and their signaling pathways and therapeutic approaches potentially targeted to human cancers.

2 Bile acid biosynthesis

BAs are the final products of cholesterol catabolism in the liver and consist of a variety of lipid-soluble acids, including cholic acid (CA), deoxycholic acid (DCA), chenodeoxycholic acid (CDCA), glycochenodeoxycholic acid (GCDCA), ursodeoxycholic acid (UDCA), glycoursodeoxycholic acid (GUDCA), glycodeoxycholic acid (GDCA), glycocholic acid (GCA), taurocholic acid (TCA), taurochenodeoxycholic acid (TCDCA), tauroursodeoxycholic acid (TUDCA), taurodeoxycholic acid (TDCA), lithocholic acid (LCA), glycolithocholic acid (GLCA), and taurolithocholic acid (TLCA) ( Li et al., 2022 ). BAs have two main ways of biosynthesis: classical and alternative synthetic pathways ( Figure 1 ) ( Chiang, 2009 ). The microsomal rate-limiting enzyme cholesterol 7α-hydroxylase (CYP7A1) initiates the classical BA synthesis pathway by which CYP7A1 oxidizes cholesterol into 7α-hydroxycholesterol. Subsequently, 3β-hydroxy∆5-C27-steroid dehydrogenase (HSD3B7) catalyzes the conversion of 7α-hydroxycholesterol to 7α-hydroxy-4-cholesten-3-one (C4), a precursor of the primary BAs, CA and CDCA. C4 also serves as a common serum biomarker used to evaluate levels of BA synthesis. Microsome sterol 12α-hydroxylase (CYP8B1) can convert C4 to 7α, 12α-dihydroxy-4-cholestene 3-1thatisfurther metabolized to be a precursor of the CA 3-alpha, 7-alpha, 12-alpha trihydroxycholestanoicacid (THCA) by aldo-keto reductases (AKR) AKR1D1/1C4 and mitochondrial sterol cholesterol 27-hydroxylase (CYP27A1). In the absence of 12α-hydroxylation, C4 undergoes conversion into 3α, 7α dihydroxycholestanoic acid (DHCA), which serves as the precursor for CDCA. THCA and DHCA are transported to peroxisomes for steroid side chain cleavage, which occurs similarly to fatty acid β-oxidation.

FIGURE 1 . The Diagram of the classical and alternative bile acid synthesis in human. Primary BAs are generated from cholesterol by the classic (CYP7A1-mediated) or alternative (CYP27A1-mediated) pathway. Subsequently, BACS and BAAT catalyze the conjugation of BAs with glycine or taurine in the liver, resulting in the formation of bile salts. Once released into the gut, these bile acids undergo modification by the gut microbiome, leading to the production of secondary BAs. Approximately 95% of the BAs that reach the terminal ileum are reabsorbed, allowing for their recycling by the liver. CYP7A1, cholesterol 7α-hydroxylase; CYP27A1, sterol 27- hydroxylase; BACS, BA-CoA synthetase; BAAT, BA-CoA: amino acid N-acyltransferase; CA, cholic acid; CDCA, chenodeoxycholic acid; CYP8B1, sterol12α-hydroxylase.

Initially, BA coenzyme A (CoA) synthase (BACS; SLC27A5) catalyzes THCA and DHCA into acyl-CoA thioesters. Subsequently, these thioesters are transported to peroxisomes through the peroxisomal BA-acyl transporter ABCD3. Among them, α-methylacyl-CoA racemase (AMACR), acyl-CoA oxidase (ACOX2), and D-bifunctional enzyme (ACOX2) are the most common enzymes. HSD17B4 completes the racemization, hydration, and dehydration steps. Finally, the sterol carrier protein x (SCPx) cleans releases propanoyl-coA from the steroid side chains of THCA and DHCA to form cholyl-coA and chenodeoxycholyl-coA, respectively. BA-coA: amino acid N-acyltransferase (BAAT) couples cholyl-coA and CDCA-coA to taurine or glycine to form T/G-CA and T/G-CDCA, respectively ( Perino et al., 2021 ).

In the alternative synthetic pathway, CYP27A1 is crucial in converting cholesterol to 27-hydroxycholesterol and 3β-hydroxy-5-cholesterol in the liver, macrophages, and adrenal glands. Oxysterol 7α-hydroxylase (CYP7B1) hydroxylates C7, resulting in the formation of 7α, 27-dihydroxycholesterol and 3β, 7α-dihydroxy-5 cholestenoic acid. In the brain, cholesterol is converted to 24-hydroxycholesterol by the enzyme sterol 24-hydroxylase (CYP46A1), which is then hydroxylated at the 7α position by a specific sterol 7α-hydroxylase (CYP39A1) in the liver. The oxysterols generated in extrahepatic tissues can serve as substrates for synthesizing CDCA and CA.

Negative feedback mechanisms tightly regulate classical and alternative BA synthesis pathways ( Di Ciaula et al., 2017 ; Collins et al., 2023 ). In human, the synthesis of BAs is primarily derived from the classical pathway, whereas approximately 50% of BAs in rodents are synthesized from the alternative pathway. CA and CDCA are the two primary BAs synthesized in the human liver. CDCA, a hydrophobic BA, undergoes further conversion to α-muricholic acid (α-MCA) by a mouse-specific enzyme sterol-6β-hydroxylase (Cyp2c70). Furthermore, α-MCA can be epimerized to be 7β-epimer, known as β-MCA. Cyp2c70 also hydroxylizes the secondary BA UDCA produced by gut bacteria to β-MCA. α-MCA and β-MCA are the primary BAs produced in rodent liver and are highly water-soluble and non-toxic. In human, bacterial 7β-hydroxysteroid dehydrogenase (7β-HSDH) converts merely 2% of CDCA as a secondary BA to the 7β-epidermoid UDCA that is a highly water-soluble and non-toxic BA.

3 The anticancer effect of natural BAs

BAs are typically appreciated as major signal molecules that act as emulsifiers in dietary lipid digestion and absorption ( Melloni et al., 2022 ). Interestingly, they are found to intervene the development of diabetes, metabolic disorders, heart disease, respiratory ailments, and tumors ( Collins et al., 2023 ; Shi et al., 2023 ). In this section, our attention primarily focuses on exploring the anticancer impacts of natural BAs ( Figure 2 .) on cancer cells in vitro (e.g., proliferation, invasion, migration, and adhesion) ( Table 1 ).

FIGURE 2 . The anticancer properties of BAs in a wide variety of cancers. UDCA, ursodeoxycholic acid; TCA, taurocholic acid; TCDCA, taurochenodeoxycholic acid; DCA, deoxycholic acid; TUDCA, tauroursodeoxycholic acid; CDCA, chenodeoxycholic acid; LCA, lithocholic acid; TDCA, taurodeoxycholic acid.

TABLE 1 . Tumor suppressive effects of natural BAs on cancers.

3.1 Glioblastoma (GB)

Glioblastoma (GB) is the most prevalent and aggressive form of adult human brain tumor. Despite the implementation of aggressive regimens involving surgery, radiation and chemotherapy, the prognosis for GBM patients remains poor with a median survival of 15 months ( Schaff and Mellinghoff, 2023 ). UDCA demonstrates the ability to penetrate through the blood-brain barrier; thus it implicates powerful activity to block brain tumor ( Palmela et al., 2015 ). Yao et al. (2020) demonstrated that UDCA inhibited GB progression in multiple aspects such as inducing G1 phase arrest, reducing mitochondrial membrane potential (MMP), promoting overproduction of reactive oxygen species (ROS), and inducing endoplasmic reticulum (ER) stress. Combining UDCA with bortezomib (BTZ) also synergistically enhances the PERK/ATF4/CHOP pathway and protracts ER stress ( Yao et al., 2020 ).

3.2 Neuroblastoma (NB)

Nephroblastoma (NB) ranks as the second most common intraabdominal cancer and the fifth most prevalent malignancy in children ( Walz et al., 2023 ). Extensive research efforts have enhanced the survival rate from less than 30% to high 85%–90%. Nevertheless, the relapse rate persists within the range of 15%–50% ( Saltzman et al., 2023 ). Strikingly, LCA effectively induced NB cell death in vitro through apoptosis without neuron cytotoxicity. This elimination was achieved by triggering the intrinsic (initiator caspase-9 activation) and extrinsic apoptosis pathways (the initiator caspase-8 activation) ( Goldberg et al., 2011 ; Trah et al., 2020 ).

3.3 Oral squamous cell carcinoma (OSCC)

Oral cancers represent prevalent malignant tumors within the head and neck and are primarily classified as squamous cell carcinomas that involve the transformation of mucous membranes in the gums, tongue, and face into cancerous tissues ( Tan et al., 2023 ). UDCA has demonstrated potential in preventing gum and periodontal dysfunctions, as well as reducing gum bleeding ( Pang et al., 2015 ). As the result, it is suggested that UDCA may hold promise in the treatment of oral cancers. Pang et al. (2015) demonstrated that UDCA triggered apoptosis in oral squamous cell cancer cells (HSC-3) via caspase activation. They also found that high UDCA levels exhibited cytotoxic effects in vitro ( Pang et al., 2015 ).

Elevated levels of BAs have been recently known to be associated with impaired immune cell function, increased patient morbidity and even mortality. Consequently, high levels of BAs are considered immune suppressors, in which TCA is the most potent one of tumor immune inhibitors ( Liu et al., 2018 ). Talebian et al. (2020) reported that TCA exhibited anti-inflammatory activities in human OSCC cells in vitro .

3.4 Oesophageal carcinoma

Esophageal carcinoma is prevalent in the developing countries and is characterized with significantly high morbidity and mortality, whereas its incidence is declining in the developed countries ( Li et al., 2023 ). Abdel-Latif et al. (2016) revealed that pretreatment with UDCA effectively inhibited DCA-induced nuclear factor kappa B (NF-κB) and activator protein-1 (AP-1) DNA-binding activities in oesophageal carcinoma cells, thus decreasing cell survival.

3.5 Cholangiocarcinoma

Cholangiocarcinoma represents a malignant tumor associated with 20%–30% rate of 5-year survival even after resection. For those unable to undergo resection, the prognosis is especially poorer in which most patients fail to survive longer than 2 years ( Greten et al., 2023 ). Although non-surgical palliative chemotherapy and radiation therapy are alternatively optional, their outcomes have not yielded satisfactory results. UDCA inhibited the growth of cholangiocarcinoma, and the combined UDCA and gefitinib displayed a more robust effect. Thus, UDCA demonstrates a potential adjuvant or palliative anticancer drug, providing a therapeutic option to enhance the effects of other chemotherapeutic agents synergistically ( Lee et al., 2022 ). UDCA suppressed cholangiocarcinoma cell proliferation and invasiveness by triggering apoptosis, activating p53, and blocking DCA-induced activated EGFR-ERK and PI3K-AKT signaling ( Lee et al., 2021 ). TUDCA impeded the proliferation of bile duct cancer cells by activating the mitogen-activated protein kinase (MAPK) p42/44 and PKCα signaling pathways ( Alpini et al., 2004 ).

3.6 Gallbladder cancer (GBC)

Gallbladder cancer is a highly malignant disease that is often misdiagnosed at early stages. Thus, rapid development of GBC at later stages has largely limited the possibility of surgical intervention, leading to a poor prognosis ( Li et al., 2014 ; Song et al., 2020a ; Geng et al., 2022 ; Wang et al., 2023a ; Wang et al., 2023b ). DCA treatment has been found to halt GBC cell proliferation and reduce miR-92b-3p expression in an m 6 A-dependent post-transcriptional modification manner by facilitating METTL3 dissociation from METTL3-METTL14-WTAP complex and thus inactivating PI3K/AKT signaling pathway ( Lin et al., 2020 ). LCA treatment has demonstrated tumor-suppressive function in GBC by decreasing glutaminase expression, interfering with glutamine metabolism and reducing GSH/GSSG and NADPH/NADP + ratios. These effects lead to cellular ferroptosis and suppress tumor growth of GBC cell lines ( Li et al., 2022 ).

3.7 Hepatocellular carcinoma (HCC)

Hepatocellular carcinoma (HCC) accounts for 85%–95% of primary liver cancer. Approximately 80% of HCC patients are diagnosed at advanced stages when surgical intervention is not applicable. The overall 5-year survival rate is less than 30% in advanced HCC patients as most of those patients with 80% experience cancer recurrence ( Brown et al., 2023 ). Consequently, there is an urgent need to elucidate the mechanisms underlying HCC progression and develop effective therapy. CDCA robustly induced the expression of N-Myc downstream-regulated gene 2 (NDRG2) to hinder the proliferation of hepatoma cells ( Langhi et al., 2013 ). Combining UDCA with anti-PD-1 enhanced anticancer immunity and promoted the development of tumor-specific immune memory. Additionally, UDCA phosphorylated transforming growth factor-beta (TGF-β) at the T282 site by activating the TGR5-cAMP-PKA axis, which increased the binding of TGF-β to the carboxyl terminus of the Hsc70-interacting protein. Combination therapy using anti-PD-1 or anti-PD-L1 antibody together with UDCA was more effective in treating tumor patients than singleanti-PD-1 or anti-PD-L1 antibody ( Shen et al., 2022 ). Combining sorafenib and UDCA chemotherapy showed efficacy in advanced HCC by inhibiting cell proliferation and inducing apoptosis through ROS-dependent activation of ERK and Stat3 dephosphorylation ( Lee et al., 2018 ). TUDCA attenuated apoptosis induced by ER stress ( Vandewynckel et al., 2015 ). UDCA suppressed HCC growth in vivo in a dose- and time-dependent apoptosis fashion by upregulating the Bax to Bcl-2 ratio, Smac , Livin and caspase-3 expressions ( Zhu et al., 2014 ; Liu et al., 2015 ), serving as a therapeutic candidate for HCC treatment. UDCA also exhibited selective ability to inhibit proliferation and induce apoptosis in HCC cell lines by disrupting the cell cycle and modulating the expression of Bax/Bcl-2 genes ( Liu et al., 2007 ). Likewise, UDCA acted as an anti-proliferative agent in HCC by inducing DLC1 protein expression and inhibiting proteasomal DLC1 degradation ( Chung et al., 2011 ). In HepG2 cells, UDCA transformed oxaliplatin-induced necrosis into apoptosis by inhibiting ROS generation and activating the p53-caspase 8 pathway. The combination of UDCA with chemotherapy effectively inhibited HCC by diminishing inflammatory responses ( Lim et al., 2010 ).

3.8 Pancreatic cancer

Pancreatic cancer shows a notably low survival rate primarily owe to late diagnosis and resistance to therapies ( Halbrook et al., 2023 ). The adverse effects of these chemotherapy treatments are also detrimental. Thus, optimal treatment remains to be developed. UDCA displayed the ability to prevent epithelial-mesenchymal transition (EMT) in pancreatic cancer cell lines, indicating its potential as an agent with antineoplastic properties ( Kim Y. J. et al., 2017 ). UDCA suppressed intracellular ROS and Prx2 levels, EMT and stem cell formation in pancreatic cancer cells. These findings suggest that UDCA’s antioxidant effects may provide favorable therapeutic benefits for patients with pancreatic cancer ( Kim Y. J. et al., 2017 ). A high BA level could inhibit cell proliferation and migration by inducing ROS and EMT pathways, thereby promoting apoptosis of pancreatic cancer cells ( Zhu et al., 2022 ). BAs could reduce the proliferation of pancreatic cancer cells due to direct cytotoxicity ( Wu et al., 2003 ). Specifically, DCA and CA induced cell cycle arrest, while GCA and TDCA elevated the S phase cell number, suggesting enhanced DNA synthesis and progression through the cell cycle ( Wu et al., 2003 ).

3.9 Gastric cancer (GC)

Gastric cancer (GC) is one of the leading causes of cancer-related mortality worldwide. Most patients are diagnosed at advanced stages due to the neglect of minimal symptoms at earlier stages and the lack of regular early screening. Systemic therapies for GC including chemotherapy, targeted therapy, and immunotherapy, have been notably practiced in recent years ( Guan et al., 2023 ). However, the favorable efficacy remains to be evaluated. TCDCA inhibited gastric cancer proliferation and invasion and induced apoptosis. Traditional Chinese medicine in experimental studies offered encouraging evidence for the potential application in the blockade of tumor ( Zhang et al., 2022 ). DCA triggered apoptosis in gastric carcinoma cells by activating intrinsic mitochondrial-dependent, p53-mediatedcell death pathway ( Yang et al., 2015 ). Furthermore, the upregulation of the Bax/Bcl-2 ratio and disruption of the mitochondrial membrane potential significantly contributed to the induction of DCA-mediated apoptosis in gastric carcinoma cells ( Song et al., 2013 ). DCA also induced MUC2 expression in GC cells, inhibiting tumor progression. Accordingly, MUC2-expressing GC cells demonstrated decreased Snail expression ( Pyo et al., 2015 ). UDCA drove apoptosis and autophagy, overcoming drug resistance ( Lim and Han, 2015 ). Additionally, UDCA and DCA demonstrated suppressive effects in gastric cancer cells by activating the ERK signaling molecules ( Lim et al., 2012 ). UDCA inhibited invasion by suppressing chenodeoxycholic acid induced PGE2 production ( Wu et al., 2018 ). Furthermore, UDCA promoted GC apoptosis by activating the death receptor 5 (DR5) in lipid rafts ( Lim et al., 2011 ).

3.10 Colon cancer

Colon cancer represents approximately 10% of all human cancers worldwide and, is also a leading cause of cancer-related deaths ( Gallois et al., 2023 ). Except the essential early diagnosis and prevention required for clinic practice, effective therapies emerge as the most powerful aspect to improve patient survival. BAs play a causal role in colon cancer by inducing DNA damage ( Kandell and Bernstein, 1991 ). TUDCA inhibited the NF-κB signaling pathway and alleviated colitis-associated tumorigenesis, indicating the valuable therapeutic means for colon cancer treatment ( Kim et al., 2019 ). DCA increased intracellular ROS, genomic DNA breakage, and expression of ERK1/2, caspase 3, and PARP. In addition, DCA inhibited colonic cell proliferation through activation in the cell cycle and apoptosis pathways ( Zeng et al., 2015 ). DCA exerted common and distinct effects on cell cycle, apoptosis, and MAP kinase pathway in human colon cancer cells ( Zeng et al., 2009 ). DCA inhibited the proliferation by inducing apoptosis through AP-1 and C/EBP-mediated GADD153 expression ( Qiao et al., 2002 ). Both DCA and CDCA suppressed cell proliferation by inducing apoptosis ( Powell et al., 2001 ). UDCA suppressed cell proliferation by regulating oxidative stress in colon cancer cells ( Kim E. K. et al., 2017 ). Treatment of colon carcinoma cells with UDCA inhibited cell proliferation by suppressing c-Myc expression and several cell cycle regulatory molecules ( Peiró-Jordán et al., 2012 ). UDCA suppressed cell growth by inhibiting the mitogenic activity of receptor tyrosine kinases such as EGFR through increased receptor degradation ( Feldman and Martinez, 2009 ). UDCA exerted a partial inhibitory effect on DCA-induced apoptosis via disrupting EGFR/Raf-1/ERK signaling pathway ( Im and Martinez, 2004 ). UDCA prevented colon tumor and polyp formation by balancing the toxic effects of DCA and enhanced the potential cytoprotective effects of muricholic acids in the water-soluble fraction in rat feces ( Batta et al., 1998 ). UDCA induced apoptosis by blocking the PI3K, MAPK, or cAMP pathways ( Saeki et al., 2012 ). UDCA inhibited interleukin β1 and blocking NF-κB and AP-1 activation in colon cells ( Shah et al., 2006 ). TUDCA augmented the cytotoxicity of hydrophobic BAs in vitro , and gaining a better understanding of how BAs interact in the colon can significantly impact the alteration of tumor promotion ( Shekels et al., 1996 ). LCA was found to activate the vitamin D receptor (VDR), blocking inflammatory signals in colon cells ( Sun et al., 2008 ). LCA also activated p53 that binds to MDM4 and MDM2, abrogating cell proliferation ( Vogel et al., 2012 ).

3.11 Breast cancer

Breast cancer continues to be the first ranked cancer in women, which is characterized by significant disease heterogeneity, metastasis, and therapeutic resistance ( Nolan et al., 2023 ). Growing evidence has found that LCA blocked breast cancer cell proliferation by stimulating oxidative stress that is under mined during breast cancer progresses ( Kovács et al., 2019 ). LCA was able to regulate lipid metabolism reprogramming to inhibit breast cancer cells ( Luu et al., 2018 ). Moreover, natural BAs negatively impacted on human breast cancer cell growth and steroid receptor function ( Baker et al., 1992 ). Like LCA in breast cancer treatment, CDCA prompted cell death and resensitized tamoxifen resistant breast cancer ( Giordano et al., 2011 ; Alasmael et al., 2016 ). Additionally, LCA exerted inhibitory effects on breast cancer proliferation, epithelial-mesenchymal transition (EMT), vascular endothelial growth factor (VEGF) production, and immune responses through the activation of the Takeda-G-protein-receptor-5 (TGR5) receptor ( Mikó et al., 2018 ).

3.12 Prostate cancer

In man, prostate cancer is ranked as the most widespread cancer globally and is the second leading cause of cancer-related mortality in most developed countries. It is of note that a significant population of elderly patients are unable to withstand the conventional chemotherapy ( Hamdy et al., 2023 ). In addition, increasing resistance to hormonal therapy has emerged as the substantial challenge in clinical treatment. Hence, alternative new drug development has been largely taken into account. LCA exhibited potent and non-selective effects on prostate cancer cells while sparing highly differentiated podocytes at lower concentrations, rendering it potential for an effective anticancer drug ( Trah et al., 2020 ). LCA induced approximately 98% of cancer cell cytotoxicity at nominal concentrations in cultured medium ( Goldberg et al., 2013 ). LCA induced autophagy and ER stress in PC-3 cells. However, this signature was found to be associated with initial protection and subsequent consequences rather than the ultimate cytotoxicity and mitochondrial dysfunction mediated by ROS ( Gafar et al., 2016 ). LCA suppressed the proliferation of androgen-dependent (AD) LNCaP prostate cancer cells by inducing an apoptotic pathway (partially dependent on caspase-8 activation). Notably, LCA increased Bid and Bax cleavage, Bcl-2 downregulation, mitochondrial outer membrane permeabilization, and caspase-9 activation. UDCA drove apoptosis in prostate cancer cells by activating extrinsic and intrinsic apoptotic pathways ( Lee et al., 2017 ). CDCA and DCA were shown to destabilize HIF-1α, significantly suppressing clonogenic growth, invasion, and migration ( Liu et al., 2016 ). CDCA inhibited prostate cancer cells via activating the Farnesoid X receptor (FXR) and upregulating phosphatase and tensin homolog (PTEN) ( Liu et al., 2014 ).

3.13 Ovarian cancer

Ovarian cancer is an aggressive disease that is often detected at advanced stages and typically exhibits a strong initial response to platinum-based chemotherapy. Despite this, the majority of patients experience relapse after the initial surgery and chemotherapy, implicating the critical necessity for the development of new therapeutic strategies ( Konstantinopoulos and Matulonis, 2023 ). CDCA and DCA exhibited noteworthy cytotoxic activity in ovarian cancer cells by inducing apoptosis ( Horowitz et al., 2007 ). CDCA and DCA could upregulate BRCA1 and downregulate ESR1 expression to inhibit BRCA1 mutated ovarian cancer progression ( Jin et al., 2018 ).

3.14 Leukemia

Leukemia represents a highly fatal hematologic malignancy characterized by the accumulation of poorly differentiated myeloid cells in the bone marrow and blood, even in other tissues and organs. This widespread feature results ultimately in systemic dysfunction ( DiNardo et al., 2023 ). To date, numerous research endeavors have been added to enhance treatment outcomes ( Kayser and Levis, 2023 ), yet the rate of complete remission remains low. CDCA suppressed acute myeloid leukemia (AML) progression by promoting both lipid droplets (LD) accumulation and lipid peroxidation via ROS/p38 MAPK/DGAT1 pathway. CDCA also inhibited the polarization of M2 macrophages, contributing to its anti-leukemic properties ( Liu et al., 2022 ). DCA, UDCA, TDCA, and TUDCA induced a delay in cell cycle progression in the human T leukemia cell line. Furthermore, DCA significantly increased the apoptotic cell fraction. DCA, CDCA and LCA inhibited the proliferation by accumulating the G0/G1 transition and inhibiting the differentiation ( Zimber et al., 1994 ). Given the hydrophobic properties of DCA accounted for its cytotoxicity, it is possible to develop its derivatives as new anti-leukemia drugs for cancer therapy ( Fimognari et al., 2009 ).

3.15 Melanoma

Melanoma has demonstrated the most lethal form of skin cancer and its incidence within the population has steadily risen in recent years. The high mortality rate of melanoma patients has continued to stimulate new research efforts to the regimens and drug development, expectedly improving the efficacy ( Carvajal et al., 2023 ). UDCA could effectively inhibit melanoma cell proliferation in a time- and dose-dependent manner through cell cycle arrest in the G2/M phase, and cell apoptosis via the ROS-triggered mitochondrial-associated pathway ( Yu et al., 2019 ).

4 Synthetic BA derivatives against cancer

Over past recent years, a large volume of researchers have paid the particular attention on modifying the structure of BAs and synthesizing derivatives in order to create novel agents to block cancers. This section mainly focuses on several synthetic derivatives of BAs that have been increasingly reported to inhibit cancer progression effectively ( Table 2 ).

TABLE 2 . Molecular targets of synthetic bile acid derivatives against cancers.

4.1 UDCA derivatives

The novel derivative HS-1030 derived from UDCA impeded hepatocellular carcinoma and breast cancer cell growth by inducing apoptosis ( Park et al., 1997 ). Similarly, HS-1183, HS-1199 and HS-1200 generated from UDCA, inhibited proliferation of acute myeloid leukemia by inducing apoptotic cell death by downregulation of caspase-3/8 ( Choi et al., 2001 ). Accordingly, these three derivatives inhibited human prostate carcinoma proliferation due to apoptosis induction via arresting cell cycle progression ( Choi et al., 2003 ). In human cervical carcinoma cells, HS-1183, HS-1199, and HS-1200 suppressed cell growth and induced apoptosis by activating the JNK and NF-κB signaling pathways ( Im et al., 2005 ). Moreover, all of HS-1030, HS-1183, HS-1199, and HS-1200 displayed the ability to inhibit colon cancer cell growth by arresting cell cycle progression at the G1 phase ( Park et al., 2004 ). Finally, HS-1183, HS-1199 and HS-1200 derivatives not only inhibited breast carcinoma cell proliferation in a dose-dependent method, but also induced apoptotic nuclear changes and sub-G1 population and DNA fragmentation through ap53-independent pathway ( Im et al., 2001 ).

In recent studies, CDCA and UDCA were conjugated with the anticancer drug paclitaxel (PTX) via a high-yield condensation reaction. The resulting product chenodeoxycholic-PTX hybrid (CDC-PTX) displayed comparable cytotoxicity and cytoselectivity to PTX. This activity was distinct from the ursodeoxycholic-PTX hybrid (UDC-PTX) that displayed limited anticancer effects on only colon cancer cells ( Melloni et al., 2022 ).

4.2 CDCA derivatives

CDCA derivatives HS-1199 and HS-1200 induced caspase-dependent apoptosis in gastric cancer cell lines. This activity was also found dependent on elevated orphan receptor Nur77 (TR3) ( Jeong et al., 2003 ). HS-1200 demonstrated an anticancer effect on human hepatoma cells as it reduced expression levels of cyclin A/D1 and Cdk2 and upregulated p21 WAF1/CIP1 and p27 KIP1 in a p53-dependent manner. HS-1200 also decreased cyclooxygenase (COX)-2 levels and induced early expression of Egr-1 ( Park S. E. et al., 2008 ). In line with these findings, HS-1200 showed potential to induce apoptosis of hepatocellular carcinoma (HCC) ( Liu et al., 2008 ). HS-1200 sensitized human breast carcinoma cells to radiation-induced apoptosis by increasing Bax expression and translocation into the mitochondria and thus increasing cytochrome c release ( Yee et al., 2007 ). Both HS-1199 and HS-1200 exerted an anticancer effect on malignant GB cells through various apoptotic manifestations, including caspase-3 activation, DNA fragmentation factor (DFF) degradation, poly (ADP-ribose) polymerase cleavage, nuclear condensation, and proteasome activity inhibition ( Yee et al., 2005 ). These two derivatives could induce apoptosis in GC cells through a caspase- and mitochondria-dependent manner ( Moon et al., 2004 ). Treatment of thyroid carcinoma cells with HS-1200 increased cell death accompanied by procaspase-3/7 degradation, ADP-ribose polymerase degradation, histone hyperacetylation and peripheral chromatin condensation ( Kim et al., 2009 ). Compound IIIb inhibited multiple myeloma cell proliferation in a way associated with Mcl-1 and PARP-1 cleavage, NF-κB signaling inhibition and/or DNA fragmentation ( El Kihel et al., 2008 ).

4.3 DCA derivatives

DCA-chalcone amides were synthesized and tested for their antitumor effects on human lung and cervical cancer cells. The studies demonstrated that specific synthesized DCA-chalcone conjugates exhibited promising outcomes to inhibit cancer cells as potential anticancer agents ( Patel et al., 2022 ). Recently, a series of new DCA derivatives were synthesized by incorporating aliphatic diamine and amino alcohol or morpholine moieties at the C3 position through 3, 26-epoxide ring-opening reactions. The mechanistic studies demonstrated that compound 9 induced cell death in colon cancer cells by activating apoptosis and autophagy. Vitamin D receptor was the primary target of this compound ( Markov et al., 2019 ).

Considerable efforts were added to investigate the anticancer effects of amino-substituted α-cyanostilbene derivatives and CA and DCA amides on the human osteosarcoma (HOS) cancer cells. These studies revealed that all CA α-cyanostilbene amides exhibited anticancer effects on HOS cells with an effective range from 2 to 13 μM through induction of apoptotic cascade ( Agarwal et al., 2018 ).

A pH-responsive micellar hydrogel system was developed using DCA-micelle (DCA-Mic) and carboxymethyl chitosan hydrogel (CMC Hyd) to improve the effectiveness of 5-FU against skin cancer and minimize side effects. This system facilitated the delivery of 5-FU into the skin and exhibited enhanced anticancer activity against melanoma cell growth compared to 5-FU alone. The 5-FU@Mic-Hyd platform showed a promising delivery system with improved efficacy for managing skin cancer in the absence of notable systemic toxicity ( Pourmanouchehri et al., 2022 ).

A conjugate of heparin with DCA exhibited cytostatic and antiangiogenic properties, enhanced the anticancer effects of Doxorubicin (DOX) on squamous cell carcinoma and melanoma cells. Furthermore, the combination treatment using these two drugs resulted in improving therapeutic efficacy while minimizing cytotoxic effects ( Park K. et al., 2008 ).

4.4 LCA derivatives

LCA and its derivatives ent-LCA induced apoptosis through CD95 activation, leading to increased ROS generation and subsequent cleavage of procaspase-8 ( Katona et al., 2009 ). A group of BA derivatives, including CA, CDCA, UDCA, and LCA against colon cancer were designed and synthesized. All the compounds exhibited an anti-proliferative signature in various human malignant tumors. Four specific compounds from 4–7 significantly inhibited colon cancer colony formation, migration, and invasion. In addition to their antitumor effects, these compounds induced apoptosis by cell cycle arresting, resulting in a blockage of the mitotic process. Furthermore, they decreased the potential of the mitochondrial membrane but increased intracellular levels of ROS. These compounds downregulated the expression of Bcl-2 and p-STAT3, contributing to their apoptotic and anti-proliferative effects. Interestingly, these compounds also exhibited anti-inflammatory activity by inhibiting the production of nitric oxide (NO) and downregulating the expression of TNF-alpha, both of which are associated with inflammation in colon cancer ( Wang et al., 2022 ).

Using LCA as a basis, ten cationic amphiphiles with variations in their head cationic charged groups were synthesized, and the anticancer effects of these amphiphiles were determined in colon cancer. LCA-based amphiphile containing piperidine head group (LCA-PIP) was approximately 10 times more cytotoxic than its precursor. The enhanced activity of LCA-PIP was attributed to a high level of cellular apoptosis. LCA-PIP induced sub-G0 arrest and caspase cleavage, promoting programmed cell death ( Singh et al., 2015 ).

A heparin-lithocholic conjugate (HL) was created by covalently bonding lithocholate to heparin, and subsequent conjugation with folate to synthesize folate-HL conjugate (FHL). Although HL and FHL showed low anticoagulant activity, they sustained antiangiogenic properties. HL and FHL demonstrated similar antiangiogenic activity and inhibition of proliferation, while FHL exhibited stronger apoptotic effects than HL. These findings highlighted the potential of FHL as an effective anticancer agent with antiangiogenic and apoptotic properties ( Yu et al., 2007 ).

LCA acetate induced leukemia cell differentiation. Combined treatment with LCA acetate and cotylenin A displayed more effectiveness in inducing monocytic differentiation than LCA acetate or cotylenin A alone. LCA acetate activated MAPK signaling that mediates cell differentiation. The synergistic effects of LCA acetate and cotylenin A on cell differentiation were partially ascribed to the MAPK activation induced by both agents ( Horie et al., 2008 ).

4.5 CA derivatives

LLC-202, a prodrug for liver cancer, was developed by conjugating oxaliplatin with CA. The conjugation was achieved using 3-NH (2) (−) cyclobutane-1,1-dicarboxylate as a linker between the oxaliplatin analog and the CA moiety. The CA component was firmly bonded to the linker via an amide bond. Compared to oxaliplatin alone, LLC-202 exhibited enhanced absorption by human liver cancer cells while showing less affinity for normal liver cells. LLC-202 possessed higher anticancer activity and efficacy than oxaliplatin through the induction of apoptosis. These findings highlighted the promising potential of LLC-202 as a liver cancer-specific prodrug ( Jiang et al., 2023 ).

A series of BAs (CA and DCA) aryl/heteroaryl amides linked with alpha-amino acid were synthesized and evaluated for the anticancer properties. More specifically, CA derivatives 6a, 6c, and 6m bearing phenyl, benzothiazole, and 4-methyl phenyl groups showed inhibitory activity against breast cancer cells compared with cisplatin and doxorubicin. Meanwhile, 6e, 6i, and 6m exhibited robust activity against the GB cancer cells relative to cisplatin and doxorubicin ( Agarwal et al., 2016 ).

4.6 Other bile derivatives

Different BA derivatives were synthesized with modified side chains and the steroid skeleton, in which the former included reaction with 2-amino-2-methylpropanol and 4,4-dimethyl oxazoline group, and cyclization of amides. The latter involved addition of steroid skeleton oxo groups in positions 7 (2, 2a, 2b) and 7,12 (3, 3a, 3b). By Wittig reaction, the ethylidene groups were introduced regio- and stereo-selectively on C-7 and without stereoselectivity on C-3. Compounds containing both C-7 ethylidene and C-12 carbonyl groups (6, 6a, and 6b) showed significant anticancer activity. Altering the carboxylic group to the amide or oxazoline group enhanced cytotoxicity ( Bjedov et al., 2017 ).

A series of new seco-A ring BA diamides were synthesized and evaluated for their anti-proliferative activities. These compounds enhanced G1 arrest and increased anti-migration activity, demonstrating improved anti-proliferative activities relative to the parent bile acid. A compound 27 conjugated with piperazine showed promising results with strong cytotoxicity in cancer cells ( Mao et al., 2016 ). Moreover, all tested compounds exhibited lower cytotoxic activity on noncancerous cells.

Fifteen new piperazinyl bile carboxamides derived from various BAs, including CA, UDCA, CDCA, DCA, and LCA, were synthesized and evaluated for their pro-apoptotic potency in colon cancer cells. Most of the synthetic bile carboxamide derivatives were found to significantly decrease cell viability, in which compound 9c and 9d exhibited the most significant dose-response effect and solubility on colon cancer cells. The presence of a benzyl group in the structure of the derivatives was associated with enhanced anti-proliferative activity. Furthermore, introducing an α-hydroxyl group at the 7-position of the steroid skeleton was particularly beneficial ( Brossard et al., 2014 ).

Two BA tamoxifen conjugates were synthesized using LCA, DCA, and CA, whereby1, 2, or 3 tamoxifen molecules were attached to the hydroxyl groups of BAs with free acid and amine functionalities in their tail regions. In these conjugates, the cholic acid-tamoxifen conjugate with a free amine headgroup (CA-Tam3-Am) demonstrated the strongest potency as an anticancer agent to induce apoptosis, cell cycle arrest, and high ROS generation. These findings highlighted that BAs could be utilized as a new framework to achieve high effective drug potency. The antitumor properties of these conjugates were significantly influenced by the charge and hydrophobicity of the lipid-drug conjugate ( Sreekanth et al., 2013 ).

Four cationic bile acid-based facial amphiphiles were synthesized and evaluated for their cytotoxic activities against colon cancer cells. The critical factors examined were charge, hydration, and hydrophobicity. Among the synthesized amphiphiles, the singly charged amphiphile based on lithocholic acid (LCA-TMA1) exhibited the highest cytotoxicity. In contrast, the triply charged cationic amphiphile based on cholic acid (CA-TMA3) showed negligible cytotoxicity. These cytotoxic effects were observed at late apoptosis. The LCA-TMA1 amphiphile demonstrated high hydrophobicity combined with a burdensome charge, leading to efficient dehydration and significant membrane perturbations. These characteristics facilitated its translocation and resulted in high cytotoxicity. On the other hand, the highly hydrated and multiple-charged amphiphile CA-TMA3 showed the least membrane penetration, limiting its translocation and subsequent cytotoxicity. Amphiphiles based on deoxycholic acid (DCA-TMA2) and chenodeoxycholic acid (CDCA-TMA2), featuring two charged head groups, displayed intermediate behavior. In conclusion, the charge, hydration, and hydrophobicity of these cationic BA-based facial amphiphiles determined their interaction with cells and membrane translocation ( Singh et al., 2013 ).

Brossard et al. (2010) utilized nitrogenous heterocycles as a fundamental component in synthesizing conjugate BA derivatives. They successfully synthesized new piperazinyl BA derivatives and examined in vitro activity in different human cancer cells. Among the synthesized derivatives, N-[4N-cinnamylpiperazin-1-yl]-3alpha,7beta-dihydroxy-5beta-cholan-24-amide (compound 7b) and N-[4N-cinnamyllpiperazin-1-yl]-3alpha,7alpha-dihydroxy-5beta-cholan-24-amide (compound 7c) demonstrated the most significant pro-apoptotic activity in these human cancer cells. These compounds induced nuclear and DNA fragmentation, indicating that 7b and 7c induce cell death through an apoptotic process. The findings suggest hybrid heterocycle-steroid compounds could serve as a new class of anticancer drugs with improved bioactivity. Additionally, the simple synthesis of these compounds highlighted their potential for future development as anticancer therapeutics ( Brossard et al., 2010 ).

Králová et al. (2008) synthesized and utilized conjugates of porphyrin and BAs as ligands to specifically bind to saccharide cancer markers expressed by tumor cells. They found that these compounds possessed a high selectivity for saccharide cancer markers and cancer cells, indicating significant potential for targeted photodynamic therapy ( Králová et al., 2008 ). LCA acetate inhibited hepatoblastoma, colon cancer and leukemia cell proliferation by binding to VDR ( Adachi et al., 2005 ). Moreover, bile-acid-appended triazolyl aryl ketones (6af and 6cf) inhibited breast cancer cell viability ( Agarwal et al., 2021 ).

5 Conclusion

This article comprehensively reviews the anticancer activities observed after treatment with both natural BAs and synthetic BA derivatives. These therapeutic approaches are attributed to the amphiphilic nature of BAs and their ability to activate additional targeted pathways that are not stimulated at physiological low concentrations. Additionally, the interaction between BAs and the gut microbiome, known as the BA/gut microbiome axis, may influence the association between BAs and cancer, facilitating BAs action ( Song et al., 2020b ).

Synthesized BA derivatives have strong ability to induce cell death in various human cancer cell lines. Consequently, these novel BA derivatives show promising results as potent agents to target different types of cancer cells by inducing apoptosis. These findings suggest that these derivatives are the potential candidates for developing novel alternative anticancer agents. Nonetheless, to better understand these agents, mechanistic insights of their activities remain to be substantially investigated. While there is currently no precise report on the cost-effectiveness of preparing BAs and their derivatives, we believe that through further research, the price of isolation, purification or synthesis expanse of BAs and derivatives can be reduced, potentially making it more affordable for a greater number of cancer patients.

Author contributions

WL: Writing–original draft. LZ: Writing–original draft. SH: Writing–review and editing. HM: Writing–review and editing. KL: Writing–review and editing. YG: Writing–review and editing, Conceptualization. YL: Writing–review and editing, Conceptualization, Writing–original draft. WW: Writing–review and editing, Conceptualization, Writing–original draft.

The author(s) declare financial support was received for the research, authorship, and/or publication of this article. This work was supported by the National Natural Science Foundation of China (Nos 82272620, 8227111000, and 82273016). Shanghai Science and Technology Innovation Action Plan (No. 22Y11908100). Open Project of State Key Laboratory of Oncogenes and Related Genes (No. KF2120), YL Expert Workstation Project of Yunnan Province (No. 202205AF150083), and the Innovative Research Team of High-level Local Universities in Shanghai.

Acknowledgments

The authors want to sincerely thank Professor Rong Shao for editing the manuscript and Figdraw for creating the figures.

Conflict of interest

The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Publisher’s note

All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.

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Keywords: bile acid biosynthesis, primary bile acid, secondary bile acid, anticancer activity, bile acid derivatives

Citation: Li W, Zou L, Huang S, Miao H, Liu K, Geng Y, Liu Y and Wu W (2024) The anticancer activity of bile acids in drug discovery and development. Front. Pharmacol. 15:1362382. doi: 10.3389/fphar.2024.1362382

Received: 28 December 2023; Accepted: 29 January 2024; Published: 20 February 2024.

Reviewed by:

Copyright © 2024 Li, Zou, Huang, Miao, Liu, Geng, Liu and Wu. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

*Correspondence: Yajun Geng, [email protected] ; Yingbin Liu, [email protected] ; Wenguang Wu, [email protected]

† These authors have contributed equally to this work

Disclaimer: All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.

Language of the gut: The unknown potential bile acids

I n a new study by the Skaggs School of Pharmacy and Pharmaceutical Sciences at UC San Diego, researchers have unveiled a vast number of previously unknown bile acids.

These discoveries shed light on the intricate communication between our gut microbiome and the rest of our body, offering unprecedented insights into human health and disease management.

Expanding our biochemical vocabulary

Senior author Pieter Dorrestein, Ph.D., compared the findings to going from basic language understanding to the complexity of Shakespeare's works. The analogy highlights a significant leap in decoding biochemical signals from our gut microbiome across our bodies.

Lee Hagey, Ph.D., a co-author and bile acids expert, described the research as a "molecular Rosetta stone." It reveals how microbes' biochemical language affects distant organs, showing their significant impact on our overall health.

The multifaceted role of bile acids

Bile acids, produced in the liver and stored in the gallbladder, are crucial for digestion. They undergo transformation by gut microbes into secondary bile acids, which are more easily absorbed by the body.

The study reveals bile acids' numerous roles beyond digestion, suggesting their use in treating various diseases. They regulate the immune system and are pivotal in metabolic processes like lipid and glucose management.

Ipsita Mohanty, Ph.D., a postdoctoral researcher and co-author, expressed her amazement at the rapid increase in bile acids identified, from merely a few hundred to several thousand. This significant growth in our understanding suggests that bile acids have numerous functions beyond aiding digestion .

Consequently, these insights open up possibilities for using bile acids in treating a diverse spectrum of illnesses, demonstrating their extensive potential in medical science.

Bile acids and disease treatment

Helena Mannochio-Russo, Ph.D., also a postdoctoral researcher in the Dorrestein lab, highlighted the wide-ranging impact of bile acids, enhanced through their symbiotic relationship with the microbiome. This effect spans well beyond mere digestion, indicating that bile acids may contribute significantly to therapies for various diseases.

Indeed, many of these potential treatments are now being investigated using bile acid-based therapies that have received FDA approval, showcasing their versatile applications in medicine.

The discovery leveraged unique resources at UC San Diego, notably the Collaborative Microbial Metabolite Center (CMMC). Under Dorrestein's leadership, the CMMC stands as a trailblazing initiative aimed at centralizing data on microbial metabolites.

This effort has been instrumental in advancing our knowledge of their effects on human health and the environment. It highlights the critical roles that collaboration and computing power play in driving forward the frontiers of modern scientific research.

Rewriting the textbook on human metabolism

With the development of a novel tool that pairs microbes with their metabolites, the research team has innovatively prepared the groundwork for further investigations. Specifically, they aim to delve into the roles of newly identified bile acids and various other critical biomolecules.

This initiative has sparked considerable excitement within the scientific community. Professor Dorrestein, a leading figure in the project, expressed his optimism regarding the upcoming phases. He emphasized the potential this tool holds for propelling rapid progress in comprehending human metabolism .

Additionally, Professor Dorrestein pointed out the significant implications for improving the treatment of various diseases. Through this breakthrough, the team anticipates a transformative impact on medical science, paving the way for groundbreaking discoveries.

The research not only marks a significant leap in our understanding of the gut microbiome's language but also opens new avenues for therapeutic interventions. It signifies a shift in the paradigm of disease treatment, moving us closer to a future where the mysteries of human metabolism are fully unveiled.

The full study was published in the journal Cell Reports .

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