Mechanisms of colon cancer chemoprevention by ursodeoxycholic acid

描述（由申请人提供）： 将要检验的假设表明，熊去氧胆酸（UDCA）通过促进受体降解抑制受体启动的促有丝分裂信号传导，发挥化学预防剂的作用。UDCA是几种胆汁酸之一，是胆固醇的极性衍生物，可调节多种癌症相关细胞间信号传导途径的活性。我们实验室最近的研究表明，胆汁酸信号激活的初始事件发生在质膜上，可能涉及膜结构域称为小窝和网格蛋白包被的小坑。已知这两种膜结构都参与通过胞吞作用沉默活化受体，胞吞作用之后是c-Cbl的泛素化和降解。我们最近的证据表明，UDCA可增强EGFR的降解，并且在存在小窝蛋白1（小窝的主要蛋白组分）的情况下，UDCA诱导的生长抑制作用增强。总之，这些观察结果表明，细胞膜可能是这种胆汁酸的靶点，UDCA可能通过抑制细胞的增殖能力发挥作用。为了检验这一点，我们将进行以下研究：（1）检验UDCA介导的EGFR降解涉及重新定位到小窝和网格蛋白包被的小窝的假设，和（2）检验UDCA是否可以在缺乏小窝蛋白的小鼠中作为化学预防剂1。

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.