BILE ACIDS AND GENE EXPRESSION IN COLON APOPTOSIS

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For almost 50 years, fecal bile acids have been implicated in playing an important role in colon carcinogenesis. This durable hypothesis has been supported by a variety of lines of evidence drawn from comparisons of the structure of bile acids to various carcinogens, epidemiological studies showing a relationship between increased fecal bile acids and colon cancer prevalence, and more recent studies demonstrating the genotoxic effects of bile acids, particularly for deoxycholic acid the predominant bile acid in stool. Despite such strong evidence linking fecal bile acids and colon cancer the mechanism of bile acid tumor promotion is not understood. Bile acids are known to induce apoptosis and since a critical step in the development of colon tumors is loss of the ability to undergo apoptosis, it has been suggested that bile acids provide a selective pressure that promotes the outgrowth of apoptosis resistant cells. Consequently, the capacity to induce apoptosis is an important activity of bile acids. Related to this, we recently showed that bile acids activate expression of GADD153, a growth arrest and DNA damage gene, that is implicated in regulating cell growth and apoptosis. The focus of this proposal is on determining the relationship between bile acid induced apoptosis, activation of (GADD153 gene expression, and bile acid tumor promotion. The hypotheses to be tested in the proposed studies are that bile acids induce apoptosis by activating the expression of GADD153 and that GADD153 becomes dysregulated in tumor cells. The specific aims are: 1) identify the cis-acting element in the GADD153 promoter that is responsive to bile acids, 2) identify the signaling pathway by which bile acids cause transactivation of the GADD153 gene and induction of apoptosis in colon cancer cells, 3) determine whether ursodeoxycholic acid, which suppresses tumor development, modifies the expression of GADD153 or the occurrence of apoptosis in preneoplastic aberrant crypt foci and in neoplasms from azoxymethane treated rats and in colonic mucosal samples and neoplasms taken from patients and from subjects treated with ursodeoxycholic acid.