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: 7074077
• 负责人: MEI LIU
• 金额: $ 0.96万
• 依托单位: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
• 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 2006-08-08
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7074077
• 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（由申请人提供）：尽管在低氧适应过程中MTOR功能的分子细节仍然非常有限，但在我们的实验室中进行的初步研究表明，该蛋白质在低氧条件下HIF-1的积累和转录激活中都起着核心作用。 对MTOR在上调PCA细胞中HIF-1转录活性中的作用的系统分析将显然增强我们对晚期前列腺癌生物学的当前理解。 通过MTOR功能的抑制剂RAPA已成为免疫抑制剂，当前建议的相关性进一步提高了。 直接证据表明，RAPA可以通过有效的抗血管生成作用进行反对癌症发展的活动，这与减少血管内皮生长因子（VEGF）的降低有关，这是HIF-1的下游靶标。 此外，RAPA类似物，CCI-779（Wyeth-Ayerst）已进入癌症患者的II期试验，并且基于鼓励初步结果，PCA被认为是主要疾病靶标。 但是，我们目前对影响PCA或其他癌细胞类型生物学的RAPA/CCI-779机制的理解水平仍然存在。 我们特别有兴趣研究RAPA处理对与PCA细胞生长和存活有关的参数的影响。 该项目的具体目标是探索：（1）定义RAPA抑制低氧细胞中稳定性HIF-1Alpha的机制，以及（2）确定RAPA的抗肿瘤活性是否与抑制小鼠中肿瘤内grop的HIF-1 Alpha功能有关。