Mechanisms of colon cancer chemoprevention by ursodeoxycholic acid

熊去氧胆酸化学预防结肠癌的机制

• 批准号: 8204971
• 负责人: JESSE D. MARTINEZ
• 金额: $ 24.13万
• 依托单位: UNIVERSITY OF ARIZONA
• 依托单位国家: 美国
• 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
• 来源: https://reporter.nih.gov/project-details/8204971
• 关键词: Animal Model; Azoxymethane; Bile Acids; CAV1 gene; Cancer Etiology; Caveolae; Cell membrane; Cells; Cessation of life; Chemopreventive Agent; Cholesterol; Clathrin; Clinical Trials; Colon Carcinoma; Colonic Neoplasms; Colonic Polyps; Colorectal Neoplasms; Development; Diagnosis; Disease; Disease Progression; Early treatment; Effectiveness; Endocytosis; Epidermal Growth Factor Receptor; Event; Growth; Laboratories; Life; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Membrane; Mus; Patients; Phase II Clinical Trials; Phosphorylation; Prevention; Prevention strategy; Property; Proteins; Research; Signal Pathway; Signal Transduction; Structure; Testing; Ubiquitination; United States; Ursodeoxycholic Acid; base; cancer chemoprevention; coated pit; public health relevance; receptor; response; ubiquitin-protein ligase

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.

描述（由申请人提供）： 将要检验的假设表明，熊去氧胆酸（UDCA）通过促进受体降解来抑制受体启动的促有丝分裂信号传导，从而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。 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，每年大约有15万新病例被诊断出来，其中大约三分之一将死于这种疾病。深入的研究表明，结肠息肉可能需要数年，甚至数十年才能发展成危及生命的恶性肿瘤，这表明早期干预可能是阻止疾病进展的最有效策略。因此，目前大力强调预防。我们的研究重点是阐明熊去氧胆酸的作用机制，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剂。我们的目标是充分了解这种药物的作用机制，以便制定更有效的预防这种致命疾病的策略，并利用这些信息，根据患者对熊去氧胆酸预防的预期反应对患者进行分层。