PI3K Pathway in Prostate Tumorigenesis and Angiogenesis

前列腺肿瘤发生和血管生成中的 PI3K 通路

• 批准号: 7037741
• 负责人: BingHua Jiang
• 金额: $ 23.4万
• 依托单位: WEST VIRGINIA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-02-01 至 2011-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7037741
• 关键词: angiogenesis; athymic mouse; carcinogenesis; chick embryo; genetic terminator element; hypoxia inducible factor 1; laboratory mouse; loss of heterozygosity; molecular oncology; neoplasm /cancer blood supply; neoplasm /cancer genetics; neoplastic growth; phosphatidylinositol 3 kinase; phosphomonoesterases; prostate neoplasms; protooncogene; serine threonine protein kinase; tissue /cell culture; tumor suppressor proteins; vascular endothelial growth factors

DESCRIPTION (provided by applicant): Accumulating evidence shows that deregulation of PI3K and PTEN signaling is important in human prostate cancers. However, the mechanisms of PI3K-induced and PTEN-inhibited prostate tumor growth are not known. The long-term objectives of this proposal are to understand the molecular mechanisms of prostate tumorigenesis due to deregulation of the PI3K and PTEN pathway, and to elucidate the connection of PI3K and PTEN downstream signaling components to tumor angiogenesis in vivo. We hypothesize that PI3K regulates prostate tumorigenesis by inducing angiogenesis in the developing tumor and by activating unexploited targets and mediators for inducing prostate tumorigenesis. Specific Aim 1 is designed to identify the mechanisms and new functions of PI3K and PTEN effectors that regulate prostate tumorigenesis using our established tumor models. This aim will study the effects of PI3K and PTEN in prostate tumor growth, test the role of angiogenesis in PI3K-induced tumor growth, and search for novel functions of PI3K effectors involved in prostate tumor growth and angiogenesis. Specific Aim 2 is designed to characterize PI3K downstream signaling molecules to transmit PI3K signals for inducing prostate tumor growth and angiogenesis. We will determine whether AKT transmits the oncogenic signals from the deregulation of PI3K and PTEN signaling, and whether AKT in turn activates p70S6K1 and MDM2 in inducing prostate tumor angiogenesis in vivo. Since we found that MDM2 is upregulated by PI3K and AKT in cultured prostate cancer cells in our preliminary study, the study of MDM2 in PI3K- and AKT-induced prostate tumorigenesis and angiogenesis will help us to understand novel mechanisms of MDM2 expression in transmiting PI3K and AKT signals for inducing the tumor angiogenesis. This work will identify new functions of PI3K effectors in prostate tumorigenesis and angiogenesis, reveal mechanisms of PI3K signaling in regulating prostate tumorigenesis, and help to establish rational therapeutic strategies for human prostate cancer by targeting specific signaling molecules in the future.

描述（由申请人提供）：积累证据表明，PI3K和PTEN信号的放松管制在人类前列腺癌中很重要。但是，尚不清楚PI3K诱导和PTEN抑制前列腺肿瘤生长的机制。该提案的长期目标是了解由于PI3K和PTEN途径导致前列腺肿瘤发生的分子机制，并阐明PI3K和PTEN下游信号传导与VIVO中肿瘤血管生成的连接。我们假设PI3K通过在发育中的肿瘤中诱导血管生成并激活未开发的靶标和介体来诱导前列腺肿瘤发生来调节前列腺肿瘤发生。特定目标1旨在确定使用我们既定的肿瘤模型来调节前列腺肿瘤发生的PI3K和PTEN效应子的机制和新功能。该目标将研究PI3K和PTEN在前列腺肿瘤生长中的影响，测试血管生成在PI3K诱导的肿瘤生长中的作用，并寻找参与前列腺肿瘤生长和血管生成的PI3K效应子的新功能。特定的目标2旨在表征下游信号分子的PI3K信号分子以传输PI3K信号，以诱导前列腺肿瘤的生长和血管生成。我们将确定AKT是否会从PI3K和PTEN信号传导中传输致癌信号，以及AKT是否会激活P70S6K1和MDM2在诱导前列腺肿瘤血管生成的体内。 Since we found that MDM2 is upregulated by PI3K and AKT in cultured prostate cancer cells in our preliminary study, the study of MDM2 in PI3K- and AKT-induced prostate tumorigenesis and angiogenesis will help us to understand novel mechanisms of MDM2 expression in transmiting PI3K and AKT signals for inducing the tumor angiogenesis.这项工作将确定PI3K效应子在前列腺肿瘤发生和血管生成中的新功能，揭示了PI3K信号在调节前列腺肿瘤发生中的机制，并有助于通过对未来的特定信号分子靶向人类前列腺癌的合理治疗策略。