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PKC Epsilon: A Novel Oncogenic Player in Prostate Cancer

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Annual rept. 1 Aug 2013-31 Aug 2014

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Protein kinase C epsilon PKCe, a member of the PKC family of phorbol esterdiacylglycerol receptors, is up-regulated in many human cancers, including prostate cancer. We recently demonstrated that PKCe is an essential mediator of NF-kB activation in prostate cancer Garg et al., JBC, 287, 37570 37582, 2012. In this research, we wish to determine if PKCe regulates TNFa-signaling to mediate its effect on NF-kB activation. Using a specific PKCe antagonist, we demonstrated that PKCe plays essential role in the TNFa-induced phosphorylation of TNF receptor in prostate cancer cells. We have previously identified that PKCe regulates NF-kB responsive genes in prostate cancer cells, including cyclooxygenase-2 COX-2 JBC, 2012. COX-2 has been reported to be up-regulated in metastatic prostate cancer. As PKCe plays an important role in prostate cancer cell survival and cooperates with other oncogenic insults, herein we aim to determine if PKCe regulates COX-2 activation during prostate tumorigenesis. In the previous funding period we have demonstrated that COX- 2 is overexpressed in human prostate cancer cell lines similar to PKCe and NF-kB. It was found that PKCe regulates COX-2 activation and PGE2 levels in prostate cancer as well as normal human prostate epithelial cells. In the present report, we present our continued efforts on the in-depth determination of the role of PKCe in COX-2 activation in prostate cancer and also to investigate if COX-2 mediates PKCe responses in prostate cancer. Our results showed that transgenic overexpression of PKCe in the mouse prostate causes preneoplastic lesions with elevated COX-2 levels. Interestingly, when we intercrossed the prostate-specific PKCe transgenic mice with mice haploinsufficient for Pten, a common genetic alteration in human prostate cancer, the resulting compound mutant mice PB-PKCePten- mice developed fully invasive adenocarcinoma with NF-kB hyperactivation and high COX-2 levels. Likewise, stable overexpression

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  • Biochemistry
  • Medicine and Medical Research

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