PI3K Pathway in Prostate Tumorigenesis and Angiogenesis

描述（由申请人提供）：越来越多的证据表明，PI3K和PTEN信号的失调在人类前列腺癌中很重要。然而，pi3k诱导和pten抑制前列腺肿瘤生长的机制尚不清楚。本课题的长期目标是了解PI3K和PTEN通路失调导致前列腺肿瘤发生的分子机制，并阐明PI3K和PTEN下游信号成分与体内肿瘤血管生成的联系。我们假设PI3K通过在肿瘤发展过程中诱导血管生成和激活未开发的靶点和介质来调节前列腺肿瘤的发生。特异性Aim 1旨在利用我们已建立的肿瘤模型，确定PI3K和PTEN效应物调节前列腺肿瘤发生的机制和新功能。本研究将研究PI3K和PTEN在前列腺肿瘤生长中的作用，检测血管生成在PI3K诱导的肿瘤生长中的作用，寻找PI3K效应物参与前列腺肿瘤生长和血管生成的新功能。特异性Aim 2旨在表征PI3K下游信号分子，传递PI3K信号，诱导前列腺肿瘤生长和血管生成。我们将确定AKT是否通过解除PI3K和PTEN信号传导致癌信号，以及AKT是否反过来激活p70S6K1和MDM2诱导体内前列腺肿瘤血管生成。由于我们在前期研究中发现，在培养的前列腺癌细胞中，MDM2被PI3K和AKT上调，因此，研究MDM2在PI3K和AKT诱导的前列腺肿瘤发生和血管生成中的作用，将有助于我们了解MDM2表达在传递PI3K和AKT信号诱导肿瘤血管生成中的新机制。本工作将进一步发现PI3K效应物在前列腺肿瘤发生和血管生成中的新功能，揭示PI3K信号调控前列腺肿瘤发生的机制，并有助于未来针对特异性信号分子建立合理的人类前列腺癌治疗策略。

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.