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

mTOR 对前列腺癌中 TGF-β/Smad 信号传导的控制

• 批准号: 7753389
• 负责人: DAVID DANIELPOUR
• 金额: $ 32.58万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-05-01 至 2014-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7753389
• 关键词: Address; Androgen Receptor; Androgens; Apoptosis; Binding; Binding Proteins; Biological; Cell Death; Cell Line; Complex; Cytostatics; Data; Development; Disease; Disease Progression; Dominant-Negative Mutation; Epithelial; Epithelial Cells; Germ Lines; Goals; Growth; Human; In Vitro; Insulin-Like Growth Factor I; Intercept; Investigation; Knockout Mice; Laboratories; Malignant - descriptor; Malignant Epithelial Cell; Malignant Neoplasms; Malignant neoplasm of prostate; Mediating; Mediation; Mediator of activation protein; Modeling; Molecular; Mullerian-inhibiting substance receptor; Nude Mice; Oncogenic; PC3 cell line; PTEN Gene Inactivation; PTEN gene; Pathway interactions; Patients; Phosphorylation; Phosphotransferases; Play; Prostate; Prostate carcinoma; Prostatic Neoplasms; Proteins; Proto-Oncogenes; Publishing; Raptors; Receptor Signaling; Regulation; Reporting; Research; Research Proposals; Role; Signal Pathway; Signal Transduction; Sirolimus; Staging; Stream; System; Testing; Therapeutic; Therapeutic Intervention; Tissues; Transforming Growth Factor beta; Transforming Growth Factor beta Receptors; Tumor Promoters; Tumor Suppressor Proteins; Withdrawal; analog; base; bone morphogenic protein; cancer cell; cell growth; in vivo; inhibitor/antagonist; insight; interest; mTOR protein; mouse model; prostate carcinogenesis; public health relevance; receptor; receptor binding; receptor function; research study; response; retroviral transduction; tumor growth; tumorigenic

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: Transforming growth factor-beta (TGF- ¿) is well recognized to function as a potent tumor suppressor of the prostate. This function of TGF- ¿ is lost in prostate through ways that remains unresolved. One way this could occur is through loss or functional inactivation of the tumor suppressor gene PTEN, reported in 30 to 50% of prostate cancers. Loss of PTEN activates tumor growth through the PI3K/Akt/mTOR signaling pathway. Our laboratory was first to report that Akt and mTOR signals intercept the ability of TGF- ¿ to suppress cell growth and induce apoptosis. We have studied components of how this may occur; however, much more effort is necessary before we can develop of clear picture of how these molecular interactions take place. In this research investigation we propose to undertake a major conceptual advance by seeking to address the more fundamental aspects of our model at a detailed molecular level, focusing on the interaction of mTOR on TGF- ¿ receptor signaling, and study the role Smads, direct mediators of TGF- ¿ and bone morphogenic proteins, in the biological activity and therapeutic action of inhibition of mTOR by rapamycin, using athymic mice as a host for growth of human prostate tumors. Understanding the molecular details behind such cross-talk is expected to substantially impact prostate cancer therapeutics.

描述（申请人提供）：mTOR对前列腺癌TGF-¿/Smad信号的控制转化生长因子- β （TGF-¿）被认为是一种有效的前列腺肿瘤抑制因子，被认为在雄激素停药后细胞死亡的激活中起关键作用。TGF-¿在前列腺癌变过程中丧失功能；然而，TGF-受体功能丧失的潜在机制仍未得到充分研究。David Danielpour博士的实验室在过去几年中进行的研究表明，胰岛素样生长因子- i （IGF-I）和雄激素受体（AR）信号通路在相当大比例的前列腺肿瘤中都被组成性激活，它们可以阻断TGF-¿信号通路的多个步骤，从而导致TGF-¿作为肿瘤抑制因子的能力丧失。IGF-I/PI3K/Akt信号通路在前列腺癌中通常通过PTEN功能丧失和/或IGF-I水平升高而激活。我们首次发表了IGF-I/PI3K/Akt通路通过依赖于哺乳动物雷帕霉素抑制剂（mTOR）的机制抑制Smads 2和3的磷酸化激活的报道。然而，mTOR介导这种抑制的机制尚不清楚，将在本提案的目标1和目标2中进行详细研究。这些目标将验证我们的假设，即mTOR复合物（TORC1）直接与TGF-¿受体相互作用并阻断TGF-¿信号通路。Aim 2将在分子水平上深入了解mTOR如何与TGF-受体相互作用并能够调节TGF-受体信号传导。我们实验室最近的数据表明，雷帕霉素对mTOR的抑制可以通过前列腺癌细胞c端磷酸化激活Smads 1、3、5或8。目的3将验证被雷帕霉素磷酸化的磷酸化Smads的身份，并验证我们的假设，即Smads 1、3、5或8在雷帕霉素对培养的前列腺癌细胞和胸腺小鼠前列腺肿瘤异种细胞生长的细胞抑制作用中起关键作用。了解PI3K/Akt/mTOR如何与TGF-¿和BMP信号相互作用，可能在前列腺癌的治疗中具有巨大的潜力。公共卫生相关性：转化生长因子- β （TGF-¿）被广泛认为是前列腺的有效肿瘤抑制因子。TGF-¿在前列腺中失去这种功能的方式尚不清楚。一种可能发生的方式是肿瘤抑制基因PTEN的丢失或功能失活，据报道在30%至50%的前列腺癌中存在。PTEN的缺失通过PI3K/Akt/mTOR信号通路激活肿瘤生长。本实验室首次报道Akt和mTOR信号阻断TGF-¿抑制细胞生长和诱导细胞凋亡的能力。我们已经研究了这可能发生的组成部分；然而，在我们能够清楚地了解这些分子相互作用是如何发生的之前，还需要做更多的努力。在这项研究调查中，我们建议通过在详细的分子水平上寻求解决我们模型的更基本方面来进行重大的概念进展，重点关注mTOR与TGF-¿受体信号的相互作用，并研究Smads （TGF-¿和骨形态发生蛋白的直接介质）在雷帕霉素抑制mTOR的生物活性和治疗作用中所起的作用，使用胸腺小鼠作为人类前列腺肿瘤生长的宿主。了解这种串扰背后的分子细节有望对前列腺癌的治疗产生重大影响。