Mammalian Target of Rapamycin in Prostate Carcinogenesis

雷帕霉素在前列腺癌发生中的哺乳动物靶点

• 批准号: 6801538
• 负责人: Jeffrey Michael Arbeit
• 金额: $ 55.98万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-09-16 至 2008-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6801538
• 关键词: angiogenesis; apoptosis; biological signal transduction; carcinogenesis; cell proliferation; chemoprevention; flavones; flow cytometry; gene expression; genetically modified animals; genistein; immunocytochemistry; in situ hybridization; laboratory mouse; messenger RNA; neoplastic growth; phosphatidylinositol 3 kinase; polymerase chain reaction; prostate neoplasms; sirolimus

DESCRIPTION (provided by applicant): Mammalian target of rapamycin (mTOR) regulates translation of a select repertoire of mRNA's controlling proliferation, cell growth and angiogenesis in response to nutritional and microenvironmental signals; mTOR also independently regulates cell survival. Mutational inactivation of upstream inhibitors and gain of function of upstream mTOR activators have been demonstrated in prostate cancer. However, the biology of mTOR function in nutritionally stressed microenvironments and in normal, neoplastic, and malignant prostate of the intact animal is unknown. In this proposal, we manipulate mTOR function in prostate cancer cells and a unique set of genetically defined prostate epithelial cell lines to determine regulation of neoplastic and malignant survival in face of provision of limited nutrients, energy substrates and oxygen. We also test bioflavonoid mTOR inhibition and response to nutrient and energy restriction. In parallel, we engineer gain of mTOR function in the prostatic epithelium of transgenic mice and use a suite of assays for histopathology, proliferation, microvascular morphology and density, apoptosis, and invasion, to test changes in prostate growth, angiogenesis, androgen responsiveness, neoplastic progression, and growth and metastatic spread of prostate cancer. Our Specific Aims are: 1. Determine whether gain or loss of PI3- kinase/AKT/mTOR function alters the ability of established prostate cancer cell lines (PC-3, LN-CAP, and DU145) to survive and/or proliferate under conditions of nutrient and oxygen stress. 2. Determine whether the nutrient-responsive mTOR-signaling pathway is a relevant molecular target for genistein and other bioflavonoid compounds implicated in prostate cancer chemoprevention. 3. Determine gain of mTOR function and alteration of prostate growth, angiogenesis, and androgen responsiveness. 4. Test gain of mTOR function and neoplastic progression in a genetic model of prostate dysplasia. 5. Test gain of mTOR function in a mouse model (probasin-SV40Tag-TRAMP) of prostate carcinogenesis, loco-regional, and distant metastasis. At completion of this proposal we will determine both molecular and biological mechanisms of mTOR function in prostate cancer cells under the dual stress of nutrient-microenvironmental substrate availability in the context of defined genetic alterations germane to human prostate carcinogenesis. Ultimately this research may suggest novel manipulations of the mTOR signaling system to either prevent or inhibit prostate cancer growth and spread.

描述（由申请人提供）： 哺乳动物雷帕霉素靶标（mTOR）调节mRNA的选择库的翻译，控制增殖、细胞生长和血管生成以响应营养和微环境信号; mTOR还独立地调节细胞存活。 上游抑制剂的突变失活和上游mTOR激活剂的功能获得已在前列腺癌中得到证实。 然而，mTOR在营养应激微环境中以及在完整动物的正常、肿瘤和恶性前列腺中的生物学功能尚不清楚。在这个提议中，我们操纵mTOR在前列腺癌细胞和一组独特的遗传定义的前列腺上皮细胞系中的功能，以确定在提供有限的营养物质、能量底物和氧气的情况下对肿瘤和恶性生存的调节。 我们还测试了生物素mTOR抑制和对营养和能量限制的反应。 与此同时，我们在转基因小鼠的前列腺上皮中设计mTOR功能的获得，并使用一套用于组织病理学、增殖、微血管形态和密度、凋亡和侵袭的测定来测试前列腺生长、血管生成、雄激素反应性、肿瘤进展以及前列腺癌的生长和转移扩散的变化。 我们的具体目标是：1。 确定PI 3-激酶/AKT/mTOR功能的获得或丧失是否会改变已建立的前列腺癌细胞系（PC-3、LN-CAP和DU 145）在营养和氧应激条件下存活和/或增殖的能力。 2.确定营养响应性mTOR信号通路是否是染料木素和其他前列腺癌化学预防中涉及的生物素化合物的相关分子靶点。 3.确定mTOR功能的获得和前列腺生长、血管生成和雄激素反应性的改变。 4.前列腺发育不良遗传模型中mTOR功能和肿瘤进展的测试增益。 5.在前列腺癌发生、局部区域和远处转移的小鼠模型（probasin-SV 40 Tag-TRAMP）中测试mTOR功能的获得。 在完成本提案后，我们将在与人类前列腺癌发生密切相关的定义的遗传改变的背景下，在营养微环境底物可用性的双重压力下，确定前列腺癌细胞中mTOR功能的分子和生物学机制。 最终，这项研究可能会提出mTOR信号系统的新操作，以预防或抑制前列腺癌的生长和扩散。