Oxidative DNA damage and apoptosis induced by bile acid: Relevance to colon cancer

Abstract

Bile acids have been linked to the etiology of colon cancer in various studies for over twenty-five years. However, the mechanism by which bile acids act in colon carcinogenesis is not known. By using an assay that can detect induction of the gadd153 stress response to DNA damage, I found that bile acids activate expression of gadd153 promoter. This observation implies that bile acids cause DNA damage. I then hypothesized that exposure of cells to bile acids produces reactive oxygen species which damage DNA. However, experiments to block gadd153 induction by bile acids using antioxidants, and to measure 8-OH-dG induced by bile acids were inconclusive. I also used p53 mutant cell lines to show that bile acid induction of apoptosis is p53-independent. In addition, my experiments showed that bile acid increased expression of gadd153 protein in HT-29 cells, and that gadd153 protein was constitutively overexpressed in HCT-116 cells with or without bile acid treatment. Thus, bile acid action in colon carcinogenesis may involve induction of DNA damage, induction of gadd153 as a protective stress response, and then if the damage is beyond repair, p53-independent apoptosis.