Apoptosis in Colon Cancer Chemoprevention

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APPLICANT'S DESCRIPTION Colon cancer remains the second leading cause of cancer death in the United States of America, affecting both males and females. The major theme of this program is the study of apoptosis in colon carcinogenesis and colon cancer chemoprevention. Studies in experimental rodent models and humans indicate that genetic and intestinal luminal risk factors decrease cell turnover, in part by decreasing apoptosis, in normal and neoplastic colonic tissues. Intestinal luminal risk factors include the secondary bile acids, which are affected by both genetic and dietary factors. Our program addresses both genetic and intestinal luminal risk factors, as we hypothesize that common signaling and metabolic pathways downstream of both these factors mediate cell turnover in colonic tissues and, subsequently, colon cancer risk. A corollary of this hypothesis is that these downstream pathways are rational targets for colon cancer chemoprevention strategies in humans. To test this hypothesis, we have designed projects and cores that are interactive and complementary. One project studies biochemical effectors of genes, including the Ki-ras oncogene and the APC and p53 tumor suppressor genes, which are frequently mutated in human colon cancers. A second project focuses on the role of nitric oxide in bile acid induced apoptosis. The third project emphasizes studies of the AP-1 transcription factor, which is involved in signaling pathways mediated by both APC and bile acids. The specific aims of the projects are to determine the roles of genetic and intestinal luminal risk factors in cell turnover in colonic tissues, to describe mechanisms underlying these processes, and to investigate the consequences of specific pharmacological and/or dietary interventions on cell turnover and colon carcinogenesis. The projects will address these aims using genetically altered cell culture and rodent models of colon cancer, and a variety of biochemical, molecular and cellular biology technologies. Four cores provide support in cell and tissue pathology, breeding and maintaining genetically altered rodent models of colon carcinogenesis, biometry and administration and evaluation. The long-term goal of the Apoptosis in Colon Cancer Chemoprevention Program Project Grant is to understand mechanisms of colon carcinogenesis in humans and then to use this information to establish the rational for strategies of colon cancer prevention and/or treatment.