title: Bile acid receptor TGR5, NADPH Oxidase NOX5-S and CREB Mediate Bile Acid-Induced DNA Damage In Barrett's Esophageal Adenocarcinoma Cells.
abstract: The mechanisms whereby bile acid reflux may accelerate the progression from Barrett's esophagus (BE) to esophageal adenocarcinoma (EA) are not fully understood. In this study we found that bile acid taurodeoxycholic acid (TDCA) significantly increased the tail moment (TM) and histone H2AX phosphorylation in FLO-1 EA cells, an increase which was significantly decreased by knockdown of TGR5. Overexpression of TGR5 significantly increased TDCA-induced TM increase and H2AX phosphorylation. In addition, NADPH oxidase inhibitor diphenylene iodonium significantly inhibited the TDCA-induced increase in TM and H2AX phosphorylation. TDCA-induced increase in TM and H2AX phosphorylation was significantly decreased by knockdown of NOX5-S and overexpression of NOX5-S significantly increased TDCA-induced increase in the tail moment and H2AX phosphorylation. Furthermore, TDCA significantly increased cAMP response element binding protein (CREB) phosphorylation in FLO-1 cells. Knockdown of CREB significantly decreased TDCA-induced increase in NOX5-S mRNA and the tail moment. Conversely, overexpression of CREB significantly increased TDCA-induced TM increase. We conclude that TDCA-induced DNA damage may depend on the activation of TGR5, CREB and NOX5-S. It is possible that in Barrett's patients bile acids may activate NOX5-S and increase reactive oxygen species (ROS) production via activation of TGR5 and CREB. NOX5-S-derived ROS may cause DNA damage, thereby contributing to the progression from BE to EA.
authors: Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Dan
authors: D
authors: Li
authors: Department of Medicine, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.|Department of Pathology, Rhode Island Hospital and Warren Alpert Medical School of Brown University, Providence, RI, USA.
authors: Weibiao
authors: W
authors: Cao
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology*; D001471:Barrett Esophagus / Q000473:pathology*; D045744:Cell Line, Tumor; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism*; D004249:DNA Damage; D005786:Gene Expression Regulation / Q000187:drug effects; D053263:Gene Regulatory Networks; D006801:Humans; D000074664:NADPH Oxidase 5 / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D013657:Taurodeoxycholic Acid / Q000378:metabolism*
chemical_list: C115163:CREB1 protein, human; D017362:Cyclic AMP Response Element-Binding Protein; C473772:GPBAR1 protein, human; D043562:Receptors, G-Protein-Coupled; D013657:Taurodeoxycholic Acid; D000074664:NADPH Oxidase 5; C431571:NOX5 protein, human