Effectors of protein kinase C-mediated tumor progression

University Of Pennsylvania, Philadelphia PA

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Abstract

? DESCRIPTION (provided by applicant): This application focuses on a novel signaling link that could have significant implications for chemoprevention and personalized therapy for prostate cancer. Specifically, we identified a functional link between the oncogenic kinase PKC? and inducible cyclooxygenase-2 (COX-2). Studies demonstrated a clear association between COX- 2 up-regulation in primary tumors, development of metastasis, and poor patient survival. There is significant evidence that inhibition of COX isoforms with non-steroidal anti-inflammatory drugs reduces risk of human cancers. In addition, COX-2 inhibitors inhibit proliferation and trigger apoptosis in prostate cancer cells, and impair prostate tumor growth in mouse models. PKC? is markedly up-regulated in prostate cancer and other cancers, and it controls key mitogenic/survival pathways such as Erk, Akt, Stat-3 and NF-?B. We generated a prostate-specific transgenic mouse model for PKC? (PB-PKC?), which develops prostatic intraepithelial neoplasia (PIN) lesions. Most remarkably, in a Pten-deficient (+/-) background, PKC? transgenic mice develop invasive prostate adenocarcinomas with Akt and NF-?B hyperactivation, and COX-2 up-regulation. Prostate epithelial cellular models engineered to recapitulate PKC? overexpression and Pten loss (i.e. PI3K hyperactivation) acquire tumorigenic potential in nude mice, become highly invasive, display COX-2 up- regulation and elevated PGE2 production (which has been linked to prostate cancer), and become highly sensitive to the killing effect of a COX-2 inhibitor. In Specific Aim 1 the main goal is to determine if COX-2 mediates PKC?-driven tumorigenesis using a number of approaches, including COX-2 shRNA silencing in PKC? expressing/Pten depleted cells orthotopically implanted in mouse prostates, treatment of PB-PKC? mice with COX-2 inhibitors, and the generation of a mouse model for prostate-specific COX-2 gene deletion in the context of PKC? overexpression. In Specific Aim 2 we will dissect the functional relevance of a link we recently identified between PKC? and the inducible PGE2 synthase mPGES-1. A dual mouse model for prostate specific PKC? overexpression in a mPGES-1-null background will be generated. The role of PGE2 (EP) receptors in driving an autocrine tumorigenic vicious cycle will be mechanistically dissected. In Specific Aim 3 we will test the hypothesis that specific p110 PI3K isoforms mediate COX-2/mPGES-1/PGE2 induction in prostate models and the tumorigenic phenotype driven by PKC? overexpression/Pten loss. Finally, to add prognostic and translational value to our studies, in Specific Aim 4 we will take advantage of a large collection of human prostate cancer specimens to determine if correlations exist between PKC? overexpression and COX-2/mPGES-1 induction. Samples with different Gleason grades, disease recurrence after prostatectomy, and castration-resistant (CRPC) disease will be used. In addition to the significant mechanistic, prognostic and therapeutic implications, our studies may provide proof-of-principle for the use of inhibitors of the COX-2/mPGES-1/EP receptor pathway for the prevention and treatment of subsets of prostate cancer patients with defined oncogenic alterations.