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.