Cox-2 Mediates Pro-Tumorigenic Effects Of Pkc Epsilon In Prostate Cancer

The pro-oncogenic kinase PKC epsilon is overexpressed in human prostate cancer and cooperates with loss of the tumor suppressor Pten for the development of prostatic adenocarcinoma. However, the effectors driving PKC epsilon-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKC epsilon overexpression acts synergistically with Pten loss to promote NF-kappa B activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKC epsilon from prostate cancer cells impaired COX-2 induction and PGE(2) production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKC epsilon, and this ability was greatly enhanced by Pten loss. Long-term COX-2 inhibition markedly reduced adenocarcinoma formation, as well as angiogenesis in a mouse model of prostate-specific PKC epsilon expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-kappa B pathway and its target gene COX2 as PKC epsilon effectors, and highlight the potential of PKC epsilon as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.