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Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review.

ABSTRACT: Bile acids are major signaling molecules that play a significant role as emulsifiers in the digestion and absorption of dietary lipids. Bile acids are amphiphilic molecules produced by the reaction of enzymes with cholesterol as a substrate, and they are the primary metabolites of cholesterol in the body. Bile acids were initially considered as tumor promoters, but many studies have deemed them to be tumor suppressors. The tumor-suppressive effect of bile acids is associated with programmed cell death. Moreover, based on this fact, several synthetic bile acid derivatives have also been used to induce programmed cell death in several types of human cancers. This review comprehensively summarizes the literature related to bile acid-induced programmed cell death, such as apoptosis, autophagy, and necroptosis, and the status of drug development using synthetic bile acid derivatives against human cancers. We hope that this review will provide a reference for the future research and development of drugs against cancer.

SUBMITTER: Jang JY

PROVIDER: S-EPMC9266679 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review.

Jang Jung Yoon JY Im Eunok E Choi Yung Hyun YH Kim Nam Deuk ND

International journal of molecular sciences 20220628 13

Bile acids are major signaling molecules that play a significant role as emulsifiers in the digestion and absorption of dietary lipids. Bile acids are amphiphilic molecules produced by the reaction of enzymes with cholesterol as a substrate, and they are the primary metabolites of cholesterol in the body. Bile acids were initially considered as tumor promoters, but many studies have deemed them to be tumor suppressors. The tumor-suppressive effect of bile acids is associated with programmed cell ...[more]

PMID: 35806184

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Project description:IntroductionCholestasis is characterized by accumulation of bile acids and inflammation, causing hepatocellular damage. Still, liver damage markers are highest in acute cholestasis and drop when this condition becomes chronic, indicating that hepatocytes adapt towards the hostile environment. This may be explained by a hormetic response in hepatocytes that limits cell death during cholestasis.AimTo investigate the mechanisms that underlie the hormetic response that protect hepatocytes against experimental cholestatic conditions.MethodsHepG2.rNtcp cells were preconditioned (24 h) with sub-apoptotic concentrations (0.1-50 μM) of various bile acids, the superoxide donor menadione, TNF-α or the Farsenoid X Receptor agonist GW4064, followed by a challenge with the apoptosis-inducing bile acid glycochenodeoxycholic acid (GCDCA; 200 μM for 4 h), menadione (50 μM, 6 h) or cytokine mixture (CM; 6 h). Levels of apoptotic and necrotic cell death, mRNA expression of the bile salt export pump (ABCB11) and bile acid sensors, as well as intracellular GCDCA levels were analyzed.ResultsPreconditioning with the pro-apoptotic bile acids GCDCA, taurocholic acid, or the protective bile acids (tauro)ursodeoxycholic acid reduced GCDCA-induced caspase-3/7 activity in HepG2.rNtcp cells. Bile acid preconditioning did not induce significant levels of necrosis in GCDCA-challenged HepG2.rNtcp cells. In contrast, preconditioning with cholic acid, menadione or TNF-α potentiated GCDCA-induced apoptosis. GCDCA preconditioning specifically reduced GCDCA-induced cell death and not CM- or menadione-induced apoptosis. The hormetic effect of GCDCA preconditioning was concentration- and time-dependent. GCDCA-, CDCA- and GW4064- preconditioning enhanced ABCB11 mRNA levels, but in contrast to the bile acids, GW4064 did not significantly reduce GCDCA-induced caspase-3/7 activity. The GCDCA challenge strongly increased intracellular levels of this bile acid, which was not lowered by GCDCA-preconditioning.ConclusionsSub-toxic concentrations of bile acids in the range that occur under normal physiological conditions protect HepG2.rNtcp cells against GCDCA-induced apoptosis, which is independent of FXR-controlled changes in bile acid transport.

Project description:UnlabelledBile acids (BAs) function as endocrine signaling molecules that activate multiple nuclear and membrane receptor signaling pathways to control fed-state metabolism. Since the detergent-like property of BAs causes liver damage at high concentrations, hepatic BA levels must be tightly regulated. Bile acid homeostasis is regulated largely at the level of transcription by nuclear receptors, particularly the primary BA receptor, farnesoid X receptor, and small heterodimer partner, which inhibits BA synthesis by recruiting repressive histone-modifying enzymes. Although histone modifiers have been shown to regulate BA-responsive genes, their in vivo functions remain unclear. Here, we show that lysine-specific histone demethylase1 (LSD1) is directly induced by BA-activated farnesoid X receptor, is recruited to the BA synthetic genes Cyp7a1 and Cyp8b1 and the BA uptake transporter gene Ntcp, and removes a gene-activation marker, trimethylated histone H3 lysine-4, leading to gene repression. Recruitment of LSD1 was dependent on small heterodimer partner, and LSD1-mediated demethylation of trimethylated histone H3 lysine-4 was required for additional repressive histone modifications, acetylated histone 3 on lysine 9 and 14 deacetylation, and acetylated histone 3 on lysine 9 methylation. A BA overload, feeding 0.5% cholic acid chow for 6 days, resulted in adaptive responses of altered expression of hepatic genes involved in BA synthesis, transport, and detoxification/conjugation. In contrast, adenovirus-mediated downregulation of hepatic LSD1 blunted these responses, which led to substantial increases in liver and serum BA levels, serum alanine aminotransferase and aspartate aminotransferase levels, and hepatic inflammation.ConclusionThis study identifies LSD1 as a novel histone-modifying enzyme in the orchestrated regulation mediated by the farnesoid X receptor and small heterodimer partner that reduces hepatic BA levels and protects the liver against BA toxicity.

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Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review.

Publications

Mechanism of Bile Acid-Induced Programmed Cell Death and Drug Discovery against Cancer: A Review.

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