Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1

Glinghammar, Björn; Inoue, H.; Rafter, Joseph

doi:10.1093/carcin/23.5.839

Cited by 114 publications

(80 citation statements)

References 38 publications

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“…At Ͼ50 M, DCA induced significant cell death, identified by visual inspection of cells and comparison of cell counts with a parallel baseline plate, fixed at the time of BA treatment. DCA is known to stimulate cell apoptosis (24). To confirm that apoptosis was not involved in the inhibitory effect of Ͻ100 M DCA on cell proliferation, cells were treated with varying doses of DCA, lysed, and probed by Western blotting for caspase-3 cleavage.…”

Section: Ba Metabolites Exert a Differential Effect On Intestinal Epimentioning

confidence: 99%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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Bile acids (BAs) are synthesized in the liver and secreted into the intestine. In the lumen, enteric bacteria metabolize BAs from conjugated, primary forms into more toxic unconjugated, secondary metabolites. Secondary BAs can be injurious to the intestine and may contribute to disease. The epidermal growth factor receptor (EGFR) and the nuclear farnesoid X receptor (FXR) are known to interact with BAs. In this study we examined the effects of BAs on intestinal epithelial cell proliferation and investigated the possible roles for EGFR and FXR in these effects. We report that taurine-conjugated cholic acid (TCA) induced proliferation, while its unconjugated secondary counterpart deoxycholic acid (DCA) inhibited proliferation. TCA stimulated phosphorylation of Src, EGFR, and ERK 1/2. Pharmacological blockade of any of these pathways or genetic ablation of EGFR abrogated TCA-stimulated proliferation. Interestingly, Src or EGFR inhibitors eliminated TCA-induced phosphorylation of both molecules, suggesting that their activation is interdependent. In contrast to TCA, DCA exposure diminished EGFR phosphorylation, and pharmacological or siRNA blockade of FXR abolished DCA-induced inhibition of proliferation. Taken together, these results suggest that TCA induces intestinal cell proliferation via Src, EGFR, and ERK activation. In contrast, DCA inhibits proliferation via an FXR-dependent mechanism that may include downstream inactivation of the EGFR/Src/ERK pathway. Since elevated secondary BA levels are the result of specific bacterial modification, this may provide a mechanism through which an altered microbiota contributes to normal or abnormal intestinal epithelial cell proliferation.

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Section: Ba Metabolites Exert a Differential Effect On Intestinal Epimentioning

confidence: 99%

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Dossa

Escobar

Golden

et al. 2016

American Journal of Physiology-Gastrointestinal and Liver Physi

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“…Phosphorylation of NF-B p65 not only enhances the efficiency of DNA binding, but also provides an additional interaction site for transcriptional co-activator CBP/p300 (29). Previous studies have shown that bile acids activate NF-B signaling pathways in cancer cells (15,30). To determine whether TCA also can activate the NF-B signaling pathways, we examined the protein levels of phosphorylated IKK␣/␤ (p-IKK␣/␤) and phosphorylated NF-B p65 (p-NF-B p65).…”

Section: Tca Induces Cox-2 Expression and Chronic Inflammation Viamentioning

confidence: 99%

Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line

Liu

Xiao

et al. 2015

Journal of Biological Chemistry

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Background: Cyclooxygenase-2 (COX-2) and sphingosine 1-phosphate receptor 2 (S1PR2) are highly expressed in human cholangiocarcinoma (CCA) and taurocholate (TCA) promotes CCA cell growth via S1PR2. Results: TCA-mediated activation of S1PR2 contributed to COX-2 expression and CCA cell growth. Conclusion: S1PR2 plays a critical role in TCA-induced COX-2 expression and CCA growth. Significance: S1PR2 represents a novel therapeutic target for CCA.

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“…Several mechanisms have been proposed to account for enhanced cell proliferation. These include activation of protooncogenes, such as c-fos and c-jun (34), and the stimulation of cyclooxygenase-2 activity (35), with the consequent increase in prostaglandin E2 production, which is involved in inducing the resistance of malignant cells to apoptosis and enhancing their invasiveness. Our results indicated that bile acid accumulation might favor cholangiocarcinoma development by stimulation of proinflammatory mechanisms and by impairing FXR-mediated chemoprotection against genotoxic insults.…”

Section: Discussionmentioning

confidence: 99%

Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

Lozano

Sanchez-Vicente

Monte

et al. 2014

Molecular Cancer Research

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Bile acid accumulation in liver with cholangiolar neoplastic lesions may occur before cholestasis is clinically detected. Whether this favors intrahepatic cholangiocarcinoma development has been investigated in this study. The E. coli RecA gene promoter was cloned upstream from Luc2 to detect in vitro direct genotoxic ability by activation of SOS genes. This assay demonstrated that bile acids were not able to induce DNA damage. The genotoxic effect of the DNA-damaging agent cisplatin was neither enhanced nor hindered by the hepatotoxic and hepatoprotective glycochenodeoxycholic and glycoursodeoxycholic acids, respectively. In contrast, thioacetamide metabolites, but not thioacetamide itself, induced DNA damage. Thus, thioacetamide was used to induce liver cancer in rats, which resulted in visible tumors after 30 weeks. The effect of bile acid accumulation on initial carcinogenesis phase (8 weeks) was investigated in bile duct ligated (BDL) animals. Serum bile acid measurement and determination of liver-specific healthy and tumor markers revealed that early thioacetamide treatment induced hypercholanemia together with upregulation of the tumor marker Neu in bile ducts, which were enhanced by BDL. Bile acid accumulation was associated with increased expression of interleukin (IL)-6 and downregulation of farnesoid X receptor (FXR). Bile duct proliferation and apoptosis activation, with inverse pattern (BDL > thioacetamide þ BDL >> thioacetamide vs. thioacetamide > thioacetamide þ BDL > BDL), were observed. In conclusion, intrahepatic accumulation of bile acids does not induce carcinogenesis directly but facilitates a cocarcinogenic effect due to stimulation of bile duct proliferation, enhanced inflammation, and reduction in FXR-dependent chemoprotection.

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Deoxycholic acid causes DNA damage in colonic cells with subsequent induction of caspases, COX-2 promoter activity and the transcription factors NF-kB and AP-1

Cited by 114 publications

References 38 publications

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Bile acids regulate intestinal cell proliferation by modulating EGFR and FXR signaling

Taurocholate Induces Cyclooxygenase-2 Expression via the Sphingosine 1-phosphate Receptor 2 in a Human Cholangiocarcinoma Cell Line

Cocarcinogenic Effects of Intrahepatic Bile Acid Accumulation in Cholangiocarcinoma Development

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