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.
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