Apoptosis occurs in response to unrepaired DNA damage. Apoptosis protects against cancer because it avoids the possibility of a cell with DNA damage replicating past the site of damage and undergoing a carcinogenic mutation. Our primary hypothesis, based on preliminary evidence and to be tested directly, is that epithelial cells, in the normal-appearing colon of patients with, or at elevated risk of developing, colon cancer, are deficient in the protective apoptosis pathway. This apparent deficiency may result from habitual eating of high-fat foods, which promotes high levels of cytotoxic bile acids/salts in the colon. Bile acids/salts damage cells of the normal colonic epithelium, causing many to undergo apoptosis. Although, initially, the loss of damaged cells by apoptosis is beneficial, chronic loss of apoptosis-sensitive cells over 30 to 40 years may select for mutant cells that are deficient in the protective apoptosis pathway. We think that long term exposure to raised concentrations of cytotoxic bile acids leads to a population of mutant colonic epithelial cells resistant to induced apoptosis. Such cells, upon exposure to dietary carcinogens, experience DNA damage, but would be unable to undergo apoptosis to avoid carcinogenesis.
The specific aims of our proposal are (1) to determine if cultured colonic epithelial cells, initially able to undergo bile acid induced apoptosis, develop stable resistance to induction of apoptosis when grown from many generations in medium containing deoxycholate; (2) to determine in rats if specific chemopreventive agents, i.e. the anti-carcinogenic bile acid ursodeoxycholic acid and the non-steroidal anti-inflammatory drugs Sulindac sulfone and aspirin prevent the development of resistance to bile acid induced apoptosis in colon epithelial cells; (3) to determine whether persons with colon cancer, or at high risk for colon cancer, have colonic epithelial cells resistant to deoxycholate induced apoptosis. Elucidation of the role of bile acid induced apoptosis, and the mechanism by which resistance to bile acid induced apoptosis develops, should give valuable insight into colon carcinogenesis. Furthermore, the measurement of resistance to bile acid induced apoptosis in colon biopsy specimens offers substantial promise as an early biomarker for colon cancer risk.
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