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。 公共卫生相关性： 结肠癌是癌症死亡的第二大原因，仅次于肺癌。在美国，每年约有15万新确诊病例，其中约三分之一将死于这种疾病。深入的研究表明，结肠息肉可能需要几年甚至几十年的时间才能发展成威胁生命的恶性肿瘤，这表明早期干预可能是阻止疾病进展的最有效策略。因此，目前非常重视预防。我们的研究集中在阐明熊去氧胆酸的机制，熊去氧胆酸是一种在II期临床试验中被证明有效的化学预防药物。我们的目标是充分了解这种药物是如何起作用的，从而开发出更有效的预防这种致命疾病的策略，并利用这些信息来帮助根据患者对熊去氧胆酸预防的预测反应来进行分层。

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.