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.
Evidence is accumulating that bile acids induce apoptosis in colonic cells. Therefore, it becomes important to study the underlying molecular mechanisms and the role of this phenomenon in tumor promotion. Minutes after exposure of HCT 116 and HT-29 cells to deoxycholate (DCA), DNA damage, measured using the COMET assay, was evident. Caspase-3 was rapidly activated in HCT 116 cells exposed to DCA, whereas in HT-29 cells, caspase-3 activation was delayed. Using transient transfections with reporter constructs, we showed that the transcription factors activator protein-1 (AP-1) and NF-kB were increased in HCT 116 cells, in a dose-dependent fashion, by DCA COX-2 promoter activity was also induced by DCA and using mutant COX-2 promoter plasmids, we showed that the ability of DCA to induce promoter activity was partly dependent upon a functional NF-kB and C/EBP site, and completely dependent on a functional c-AMP response element site. DNA damage thus appears to be the initiating event in DCA-induced apoptosis. In conclusion, the bile acid, DCA, has a major impact on apoptotic mechanisms in colonic cells and this may be contributing to its effect as a tumor promoter.
Glinghammar
B
B
Department of Medical Nutrition, Karolinska Institutet, Novum, S-141 86 Huddinge, Sweden.
Inoue
H
H
Rafter
J J
JJ
D017209:Apoptosis; D053148:Caspase 3; D061945:Caspase Inhibitors; D020169:Caspases / Q000096:biosynthesis* / Q000378:metabolism; D002460:Cell Line; D003106:Colon / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D020552:Comet Assay; D051546:Cyclooxygenase 2; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D004247:DNA / Q000187:drug effects*; D004249:DNA Damage; D003840:Deoxycholic Acid / Q000494:pharmacology*; D004789:Enzyme Activation; D004790:Enzyme Induction; D007527:Isoenzymes / Q000235:genetics*; D016328:NF-kappa B / Q000096:biosynthesis* / Q000502:physiology; D011401:Promoter Regions, Genetic; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D018808:Transcription Factor AP-1 / Q000096:biosynthesis* / Q000502:physiology; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007527:Isoenzymes; D016328:NF-kappa B; D018808:Transcription Factor AP-1; D003840:Deoxycholic Acid; D004247:DNA; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D053148:Caspase 3; D020169:Caspases