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
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
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DOI：
10.1093/carcin/23.5.839
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发表时间：
2002-05-01
期刊：
影响因子：
4.7
通讯作者：
Rafter, JJ
中科院分区：
文献类型：
--
作者：
Glinghammar, B;Inoue, H;Rafter, JJ
越来越多的证据表明胆汁酸可以诱导结肠细胞的凋亡。因此，研究这一现象的潜在分子机制及其在肿瘤促进中的作用变得非常重要。用脱氧胆酸盐(DCA)暴露于HCT 116和HT-29细胞几分钟后，用彗星试验测量的DNA损伤是明显的。DCA作用于HCT 116细胞后，caspase-3迅速激活，而在HT-29细胞中，caspase-3激活延迟。通过瞬时报告基因的构建，我们发现DCA诱导HCT 116细胞中转录因子激活蛋白-1(AP-1)和核因子-kB的表达呈剂量依赖关系，DCA诱导的COX-2启动子活性也被DC A和突变的COX-2启动子载体所诱导。我们发现DCA诱导启动子活性的能力部分依赖于一个功能性的NF-kB和C/EBP位点，完全依赖于一个功能性的c-AMP反应元件位点。因此，DNA损伤似乎是DCA诱导细胞凋亡的始动事件。总之，胆汁酸DCA对结肠细胞的凋亡机制有重要影响，这可能是其作为肿瘤促进剂的作用之一。
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 DC A 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.