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

项目总结： MTOR在前列腺癌中对转化生长因子β/Smad信号的调控 转化生长因子-β(TGF-β)被公认为是一种有效的肿瘤 前列腺抑制因子，被认为在激活细胞死亡中起着关键作用 在雄激素停用后。转化生长因子-β在肿瘤发生发展过程中的功能缺失 然而，这种转化生长因子受体功能丧失的潜在机制仍然存在 研究很少。过去几年在大卫·丹尼尔普尔博士的实验室进行的研究 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，似乎在相当大的比例中被结构性激活 前列腺癌可以阻断转化生长因子-β信号通路的多个步骤，从而促进 失去了转化生长因子-β作为肿瘤抑制因子的功能。IGF-I/PI3K/Akt信号转导 在前列腺癌中，通路通常通过PTEN功能和/或缺失而被激活 IGF-I水平升高。我们首次报道了IGF-I/PI3K/Akt通路 抑制Smads 2和3的磷酸化，其机制依赖于 雷帕霉素的哺乳动物抑制剂(MTOR)。然而，mTOR的机制 调解这种压制是未知的，将按照的目标1和2进行详细调查 这项提议。这些目标将检验我们的假设，即mTOR复合体(TORC1)直接 与转化生长因子受体相互作用，阻断转化生长因子-β信号通路。目标2将会发展 在分子水平上对mTOR如何与转化生长因子β相互作用的实质性机械洞察 并且能够调节转化生长因子受体的信号转导。我们实验室的最新数据 提示雷帕霉素通过抑制mTOR激活Smad 1、3、5或8。 前列腺癌细胞系中的末端磷酸化。Aim 3将验证 被雷帕霉素磷酸化的Smads，并测试我们的假设Smads 1， 3、5或8在介导雷帕霉素对前列腺癌细胞的细胞抑制作用中起关键作用 在裸鼠前列腺癌异种移植瘤的培养和生长中。了解 PI3K/Akt/mTOR与这些转化生长因子和骨形态发生蛋白信号的交叉对话可能会有实质性的 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.