Mechanisms of colon cancer chemoprevention by ursodeoxycholic acid

描述(由申请人提供)： 将被检验的假说表明，熊去氧胆酸(UDCA)通过促进受体降解来抑制受体启动的有丝分裂信号，从而起到化学预防的作用。UDCA是几种胆汁酸之一，胆汁酸是胆固醇的极性衍生物，可以调节多种与癌症相关的细胞间信号通路的活性。我们实验室最近的研究表明，胆汁酸激活信号的最初事件发生在质膜上，可能涉及被称为小窝和笼状蛋白涂层小窝的膜域。已知这两种膜结构都参与了通过内吞作用沉默激活的受体，随后c-Cbl泛素化和降解。我们最新的证据表明，UDCA促进了EGFR的降解，并且UDCA诱导的生长抑制在小窝的主要蛋白质成分小窝1的存在下得到加强。总之，这些观察结果表明，细胞膜可能是这种胆汁酸的靶标，UDCA可能通过抑制细胞的增殖能力发挥作用。为了验证这一点，我们将进行以下研究：(1)测试UDCA介导的EGFR降解涉及重新定位到小窝和覆膜小窝的假设，以及(2)测试UDCA是否可以作为缺乏小窝蛋白1的小鼠的化学预防性药物。

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.