Role of mTOR in Hypoxic Adaptation in Prostate Cancer

mTOR 在前列腺癌缺氧适应中的作用

• 批准号: 7278970
• 负责人: MEI LIU
• 金额: $ 4.84万
• 依托单位: ROTHBERG INSTITUTE, INC.
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-06-01 至 2007-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7278970
• 关键词: SCID mouse; SDS polyacrylamide gel electrophoresis; analog; angiogenesis inhibitors; antineoplastics; biological signal transduction; enzyme activity; gene expression; genetic transcription; hypoxia; hypoxia inducible factor 1; immunoprecipitation; kinase inhibitor; mass spectrometry; neoplastic cell; phosphorylation; postdoctoral investigator; prostate neoplasms; protein degradation; protein kinase; protein structure function; sirolimus; transcription factor; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Although the molecular details of mTOR function during the hypoxic adaptation remain very limited, preliminary studies performed in our laboratory indicated that this protein plays central roles in both the accumulation and transcriptional activation of HIF-1 under hypoxic conditions. A systematic analysis of the role of mTOR in upregulating HIF-1 transcriptional activity in PCa cells will clearly enhance our current understanding of the biology of late-stage prostate cancer. The relevance of the current proposal is further increased by the fact that inhibitor of mTOR function, RAPA is already in the clinic as an immunosuppressive agent. Direct evidence has emerged that RAPA could have activities against cancer development through a potent anti-angiogenic action, which is linked to reduction of vascular endothelial growth factor (VEGF), a downstream target of HIF-1. Furthermore, a RAPA analog, CCI-779 (Wyeth-Ayerst) has entered Phase II trials in cancer patients, and, based on encouraging preliminary results, PCa is considered a prime disease target. However, our current level of understanding regarding the mechanisms of RAPA/CCI-779 affecting the biology of PCa or other cancer cell types remains at an early stage. We are particularly interested in studying the impact of RAPA treatment on parameters related to the growth and survival of PCa cells. The specific objectives of this project are to explore: (1) to define the mechanism by which RAPA inhibits stabilization HIF-1alpha in hypoxic cells and (2) to determine whether the antitumor activity of RAPA is linked to inhibition of HIF-1 alpha function in tumor xenograft in mice.

描述（申请人提供）：虽然在缺氧适应过程中mTOR功能的分子细节仍然非常有限，但我们实验室进行的初步研究表明，该蛋白在缺氧条件下HIF-1的积累和转录激活中发挥着核心作用。 对 mTOR 在 PCa 细胞中上调 HIF-1 转录活性中的作用进行系统分析将明显增强我们目前对晚期前列腺癌生物学的理解。 mTOR 功能抑制剂 RAPA 已经作为免疫抑制剂进入临床，这一事实进一步增加了当前提案的相关性。 直接证据表明，RAPA 可能通过有效的抗血管生成作用来对抗癌症发展，这与 HIF-1 下游靶点血管内皮生长因子 (VEGF) 的减少有关。 此外，RAPA 类似物 CCI-779 (Wyeth-Ayerst) 已进入癌症患者的 II 期试验，并且基于令人鼓舞的初步结果，PCa 被认为是主要的疾病目标。 然而，我们目前对 RAPA/CCI-779 影响 PCa 或其他癌细胞类型生物学机制的了解仍处于早期阶段。 我们特别感兴趣的是研究 RAPA 治疗对 PCa 细胞生长和存活相关参数的影响。 该项目的具体目标是探索：(1) 明确 RAPA 抑制缺氧细胞中 HIF-1α 稳定的机制；(2) 确定 RAPA 的抗肿瘤活性是否与抑制 HIF-1 α 功能有关在小鼠肿瘤异种移植中。