Abstract
Abstract Protein kinase C epsilon (PKCϵ), a member of the PKC family of phorbol ester/diacylglycerol receptors, has emerged as an oncogenic kinase and plays important role in cell survival, mitogenesis and invasion. PKCϵ is up-regulated in most epithelial cancers, including prostate cancer. We recently showed that transgenic PKCϵ overexpression in the mouse prostate under the control of probasin (PB) promoter leads to hyperplasia and prostatic intraepithelial neoplastic lesions but is insufficient to drive neoplastic changes. Strikingly, 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prostate cancer, the resulting compound mutant mice (PB-PKCϵ;Pten+/- mice) developed fully invasive adenocarcinoma (unpublished observation). In the present study, to explore the mechanistic aspects of the observed cooperativity between PKCϵ overexpression and Pten deficiency, we stably overexpressed PKCϵ in mouse prostate epithelial lines that are either heterozygous (P8) or homozygous (CaP8) for Pten deletion. PKCϵ overexpression led to significant enhancement in cell proliferation as well as enhanced the levels of phospho-Akt, phospho-Erk and phospho-mTOR; these effects are more pronounced in CaP8 cells. Moreover, migration, invasion, clonogenic and soft agar colony formation assays revealed a striking synergism between PKCϵ overexpression and Pten loss. Furthermore, analysis of global gene expression by microarray revealed significant changes in gene related to EMT, adhesion, metabolism, and invasiveness following PKCϵ overexpression, Pten loss or both. In particular, a chemokine CXCL13 was found to be majorly up-regulated in CaP8-PKCϵ cells. Measurement of CXCL13 mRNA by qPCR or CXCL13 release to the conditioned medium (CM) by ELISA showed increased levels in PKCϵ overexpressing or Pten depleted cells, and these effects were synergistically enhanced in CaP8-PKCϵ cells. Remarkably, CM from CaP8-PKCϵ cells led to significant induction in growth and motility of P8 cells. Importantly, CXCL13 RNAi depletion reduced the proliferative and migratory capacity of CaP8-PKCϵ cells, thereby establishing the potential relevance of CXCL13 in the phenotypic effects of PKCϵ overexpression and Pten loss. Concurrently, the growth and motile activity of P8 cells were enhanced in response to exogenously added CXCL13. Overall, our results argue for the role of CXCL13 in mediating effects of oncogenic PKCϵ in prostate cancer. Citation Format: Rachana Garg, Martin Abba, Marcelo G. Kazanietz. CXCL13 as a mediator of oncogenic PKCϵ in prostate cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 1596. doi:10.1158/1538-7445.AM2014-1596
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