Abstract LB-154: COX-2 as a mediator of oncogenic PKCε in prostate cancer.

Abstract

Abstract Protein kinase C epsilon (PKCε), a member of the PKC family of phorbol ester/diacylglycerol receptors, is up-regulated in many human cancers, including prostate cancer. We recently demonstrated that PKCε is an essential mediator of NF-κB activation in prostate cancer (Garg et al., JBC, 287 (44), 37570–37582, 2012). Cyclooxygenase-2 (COX-2), a well-known NF-κB regulated gene, has been reported to be up-regulated in a number of human cancers, including metastatic prostate cancer. As PKCε plays an important role in prostate cancer cell survival and cooperates with other oncogenic insults, herein we aim to determine if PKCε regulates COX-2 activation during prostate tumorigenesis. PKCε RNAi depletion diminishes TNFα- or LPS-induced COX-2 mRNA expression in LNCaP prostate cancer cells and constitutive COX-2 levels from PC3 cells. Conversely, PKCε overexpression by adenoviral means potentiates TNFα or LPS-induced COX-2 expression in LNCaP cells. Notably, transgenic overexpression of PKCε in the mouse prostate causes preneoplastic lesions with elevated COX-2 levels. Interestingly, when we intercrossed the prostate-specific PKCε transgenic mice with mice haploinsufficient for Pten, a common genetic alteration in human prostate cancer, the resulting compound mutant mice (PB-PKCε;Pten+/− mice) developed fully invasive adenocarcinoma with NF-κB hyperactivation and high COX-2 levels. Likewise, stable overexpression of PKCε in mouse prostate epithelial cell lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion, led to significant enhancements in cell proliferation, motility and invasiveness as well as in LPS-induced COX-2 mRNA expression compared to the respective control cells, and this effect is more pronounced in CaP8 cells. Studies using human prostate tumors revealed a co-existence of PKCε overexpression, NF-κB hyperactivation, and COX-2 up-regulation. Lastly, treatment of PKCε overexpressing P8 or CaP8 cells with the selective COX-2 inhibitor NS398 caused a pronounced growth inhibition. Overall, our study identified COX-2 as a PKCε-regulated gene. Our results suggest that COX-2 as a potential mediator of PKCε oncogenesis in prostate cancer, particularly in the context of Pten loss. Citation Format: Rachana Garg, Priti Lal, Jorge Blando, Fernando J. Benavides, Michael D. Feldman, Emer M. Smyth, Marcelo G. Kazanietz. COX-2 as a mediator of oncogenic PKCε in prostate cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-154. doi:10.1158/1538-7445.AM2013-LB-154