# Effectors of protein kinase C-mediated tumor progression

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2020 · $389,662

## 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 PKCε 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. PKCε 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-κB. We generated a prostate-specific transgenic mouse model for PKCε (PB-PKCε), which develops prostatic intraepithelial neoplasia (PIN) lesions. Most remarkably, in a Pten-deficient (+/-) background, PKCε transgenic mice develop invasive prostate adenocarcinomas with Akt and NF-κB hyperactivation, and COX-2 up-regulation. Prostate epithelial cellular models engineered to recapitulate PKCε 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 PKCε-driven tumorigenesis using a number of approaches, including COX-2 shRNA silencing in PKCε expressing/Pten depleted cells orthotopically implanted in mouse prostates, treatment of PB-PKCε mice with COX-2 inhibitors, and the generation of a mouse model for prostate-specific COX-2 gene deletion in the context of PKCε overexpression. In Specific Aim 2 we will dissect the functional relevance of a link we recently identified between PKCε and the inducible PGE2 synthase mPGES-1. A dual mouse model for prostate specific PKCε 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 PKCε 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 PKCε 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 mechan...

## Key facts

- **NIH application ID:** 9836791
- **Project number:** 5R01CA196232-05
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Marcelo G. Kazanietz
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $389,662
- **Award type:** 5
- **Project period:** 2016-01-01 → 2022-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9836791

## Citation

> US National Institutes of Health, RePORTER application 9836791, Effectors of protein kinase C-mediated tumor progression (5R01CA196232-05). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/9836791. Licensed CC0.

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