Mechanisms of colon cancer chemoprevention by ursodeoxycholic acid

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DESCRIPTION (provided by applicant): The hypothesis that will be tested suggests that ursodeoxycholic acid (UDCA) functions as a chemopreventive agent through the suppression of receptor-initiated mitogenic signaling by promoting receptor degradation. UDCA is one of several bile acids which are polar derivatives of cholesterol that can modulate the activity of a variety of cancer related interacellular signaling pathways. Recent studies from our laboratory indicate that the initial events in signal activation by bile acids take place at the plasma membrane and may involve membrane domains known as caveolae and clathrin coated pits. Both of these membrane structures are known to be involved in silencing of activated receptors through endocytosis which is followed by ubiquitination by c-Cbl and degradation. Our most recent evidence suggests that UDCA enhances degradation of EGFR and that UDCA-induced growth suppression is enhanced in the presence of caveolin1, a principal protein component of caveolae. Together these observations suggest that the cell membrane is a likely target for this bile acid and that UDCA may act by suppressing the proliferative capacity of cells. To test this we will conduct the following studies: (1) Test the hypothesis that UDCA-mediated degradation of EGFR involves relocalization to caveolae and clathrin coated pits, and (2) Test whether UDCA can function as a chemopreventive agent in mice that lack caveolin1. PUBLIC HEALTH RELEVANCE: Colon cancer is the second leading cause of cancer deaths being second only to lung cancer. Approximately 150,000 new cases are diagnosed each year in the United States and about one third of those will die of their disease. Intensive research has shown that colon polyps may take years, perhaps decades, to develop into life threatening malignancies which suggest that early intervention may be the most effective strategy for stopping progression of the disease. Hence, there is currently a strong emphasis on prevention. Our studies focus on elucidating the mechanism of ursodeoxycholic acid a chemopreventive agent that has proven effective in phase II clinical trials. Our objective is to develop sufficient understanding of how this agent acts so as to develop more effective strategies for prevention of this deadly disease and to utilize this information to help stratify patients based on their projected response to prevention with ursodeoxycholic acid.