Control of TGF-Beta/Smad Signaling by mTOR in Prostate Cancer

项目摘要： 前列腺癌中mTOR对TGF-β/Smad信号通路的调控 转化生长因子-β（TGF-β）被公认为是一种有效的肿瘤 前列腺的抑制因子，据信在细胞死亡的激活中起关键作用 雄激素戒断后 TGF-β的功能在肿瘤的发生过程中丧失， 前列腺;然而，这种TGF-β受体功能丧失的潜在机制仍然存在， 研究得不好。 大卫丹尼尔普尔博士实验室在过去几年里进行的研究 已经证明胰岛素样生长因子-I（IGF-I）和雄激素受体 (AR)信号通路，这似乎是组成性激活的相当大的比例， 前列腺肿瘤，可以阻断TGF-β信号通路中的多个步骤，从而有助于 TGF-β作为肿瘤抑制因子的功能丧失。IGF-I/PI 3 K/Akt信号通路 在前列腺癌中，通常通过PTEN功能的丧失和/或 IGF-I水平升高。 我们首次发表了IGF-I/PI 3 K/Akt信号通路的研究报告， 抑制Smads 2和3的磷酸化激活，通过依赖于 哺乳动物雷帕霉素抑制剂（mTOR）。 然而，mTOR的机制 介导这种抑制是未知的，并将进行调查，如详细的目标1和2， 这个提议。 这些目标将检验我们的假设，即mTOR复合物（TORC 1）直接 与TGF-β受体相互作用并阻断TGF-β信号通路。 Aim 2将开发 mTOR如何与TGF-β相互作用的分子水平上的实质性机制见解 受体，并能够调节TGF-β受体信号传导。 我们实验室的最新数据 表明雷帕霉素对mTOR的抑制通过它们的c- 前列腺癌细胞系中的末端磷酸化。 目标3将验证 磷酸-Smads被雷帕霉素磷酸化，并测试我们的假设，Smads 1， 3、5或8对于介导雷帕霉素对前列腺癌细胞的细胞抑制作用是关键的 在培养物和无胸腺小鼠前列腺肿瘤异种移植物的生长中。了解 PI 3 K/Akt/mTOR如何与那些TGF-β和BMP信号转导进行交叉对话， 前列腺癌的治疗潜力。

Project Summary: Control of TGF-¿/Smad Signaling by mTOR in Prostate Cancer Transforming growth factor-beta (TGF-¿) is well recognized to function as a potent tumor suppressor of the prostate, where it is believed to play a pivotal role in activation of cell death following androgen withdrawal. The function of TGF-¿ is lost during carcinogenesis of the prostate; however, the underlying mechanisms for this loss of TGF-¿ receptor function remain poorly studied. Studies conducted in Dr. David Danielpour's laboratory in the past several years have demonstrated that both the insulin-like growth factor-I (IGF-I) and the androgen receptor (AR) signaling pathways, which appear to be constitutively activated in a sizable proportion of prostate tumors, can block multiple steps in the TGF-¿ signaling pathway and thus contribute to loss of the ability of TGF-¿ to function as a tumor suppressor. The IGF-I/PI3K/Akt signaling pathway is commonly activated in prostate cancer through loss of PTEN function and/or elevation of IGF-I levels. We published the first reports that the IGF-I/PI3K/Akt pathway suppresses phospho-activation of Smads 2 and 3 through a mechanism that is dependent on the mammalian inhibitor of rapamycin (mTOR). However, the mechanism by which mTOR mediates such suppression is not known, and will be investigated as detailed in Aims 1 and 2 of this proposal. These aims will test our hypothesis that an mTOR complex (TORC1) directly interacts with TGF-¿ receptors and intercepts the TGF-¿ signaling pathway. Aim 2 will develop substantial mechanistic insight at the molecular level of how mTOR interacts with TGF-¿ receptors and is able to modulate TGF-¿ receptor signaling. Recent data from our laboratory suggests that inhibition of mTOR by rapamycin activates Smads 1, 3, 5 or 8 through their c- terminal phosphorylation in prostate cancer cell lines. Aim 3 will validate the identity of the phospho-Smads that are phosphorylated by rapamycin, and test our hypothesis that Smads 1, 3, 5 or 8 are critical to mediation of the cytostatic effects of rapamycin on prostate cancer cells in culture and in growth of prostate tumor xenographs in athymic mice.. Understanding the how PI3K/Akt/mTOR cross-talks with those TGF-¿ and BMP signaling will likely have substantial therapeutic potential in prostate cancer.