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Mechanisms of colon cancer chemoprevention by ursodeoxycholic acid

熊去氧胆酸化学预防结肠癌的机制

基本信息

批准号：
8601360
负责人：
JESSE D. MARTINEZ
金额：
$ 6.9万
依托单位：
UNIVERSITY OF ARIZONA
依托单位国家：
美国
项目类别：
财政年份：
2010
资助国家：
美国
起止时间：
2010-01-01 至 2013-12-31
项目状态：
已结题

项目摘要

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.

描述（由申请人提供）：将要测试的假设表明，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，从而发挥化学预防剂的作用。 UDCA 是几种胆汁酸之一，胆汁酸是胆固醇的极性衍生物，可以调节多种癌症相关的细胞间信号传导途径的活性。我们实验室的最新研究表明，胆汁酸信号激活的初始事件发生在质膜上，并且可能涉及称为小窝和网格蛋白包被小坑的膜域。已知这两种膜结构都通过内吞作用参与激活受体的沉默，随后被 c-Cbl 泛素化并降解。我们最新的证据表明，UDCA 会增强 EGFR 的降解，并且在 Caveolae 的主要蛋白质成分 Caveolin1 存在的情况下，UDCA 诱导的生长抑制会增强。这些观察结果表明，细胞膜可能是这种胆汁酸的目标，并且 UDCA 可能通过抑制细胞的增殖能力发挥作用。为了测试这一点，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网格蛋白包被小凹的假设，以及 (2) 测试 UDCA 是否可以在缺乏小窝蛋白的小鼠中充当化学预防剂1。