Prostate cancer is one of the most commonly diagnosed malignancies and the second leading cause of cancer-related deaths among men in the United States. Protein kinase C epsilon (PKCϵ), a member of the PKC family of phorbol ester/diacylglycerol receptors, has emerged as an oncogenic kinase and shown to be up-regulated in human prostate cancer specimens. We recently demonstrated that PKCϵ is an upstream regulator of NF-κB activation in prostate cancer (JBC, 287:37570-37582, 2012) and that transgenic overexpression of PKCϵ in mice prostate under the control of the probasin promoter (PB-PKCϵ) leads to hyperplasia and PIN lesions but was insufficient to drive neoplastic changes (Cell Cycle, 10:268-277, 2011). Notably, when we intercrossed PB-PKCϵ mice with mice haploinsufficient for Pten, another common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCϵ;Pten+/- mice) developed fully invasive adenocarcinoma with elevated NF-κB levels. In the present study, we aim to delineate the mechanism underlying the observed cooperativity between PKCϵ overexpression and Pten deficiency and to explore the consequences of this cooperativity on the transcription factor NF-κB signaling, a pathway known to be highly dysregulated in prostate tumorigenesis. To this end, we stably overexpressed PKCϵ in mouse prostate epithelial lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion. We observed a striking synergism between PKCϵϵ overexpression and Pten loss in conferring enhanced proliferative, migratory and invasive phenotype. Moreover, LPS or TNFα stimulation of these cells led to increased NF-κB activation as evident from the elevated IκBα phosphorylation, NF-κB nuclear translocation and transactivation of a NF-κB luciferase reporter. These effects were much more pronounced in CaP8 cells. Of note, PKCϵ overexpression and Pten loss also cooperates to augment levels of the NF-κB regulated gene, COX-2. Stable overexpression of PKCϵ and Pten depletion in “normal” immortalized RWPE1 cells also resulted in significant enhancements in TNFα-induced NF-κB activation and COX-2 induction. Furthermore, NF-κB inhibition by parthenolide significantly retarded the growth of CaP8-PKCϵ tumors in athymic nude mice. Overall, our results identify NF-κB as a mediator of PKCϵ oncogenesis in prostate cancer, particularly in the context of Pten loss.
Citation Format: Rachana Garg, Jorge Blando, Carlos J. Perez, Fernando J. Benavides, Marcelo G. Kazanietz. Protein kinase C ϵ cooperates with Pten deficiency to regulate NF-κB pathway in prostate cancer progression. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 799. doi:10.1158/1538-7445.AM2015-799