COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer

Oncogene
Rachana GargMarcelo G Kazanietz

Abstract

The pro-oncogenic kinase PKCε 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 PKCε-mediated phenotypes remain poorly defined. Here, using cellular and mouse models, we showed that PKCε overexpression acts synergistically with Pten loss to promote NF-κB activation and induce cyclooxygenase-2 (COX-2) expression, phenotypic traits which are also observed in human prostate tumors. Targeted disruption of PKCε from prostate cancer cells impaired COX-2 induction and PGE2 production. Notably, COX-2 inhibitors selectively killed prostate epithelial cells overexpressing PKCε, 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 PKCε expression and Pten loss. Overall, our results provide strong evidence for the involvement of the canonical NF-κB pathway and its target gene COX2 as PKCε effectors, and highlight the potential of PKCε as a useful biomarker for the use of COX inhibition for chemopreventive and/or chemotherapeutic purposes in prostate cancer.

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Citations

Apr 6, 2019·Anti-cancer Agents in Medicinal Chemistry·Vladimir S RogovskiiNikolai L Shimanovskii
Jul 10, 2019·Journal of Cellular and Molecular Medicine·Yuan-Yuan ChenZhong-Ning Lin
Jul 30, 2019·Frontiers in Endocrinology·Marcelo G KazanietzMariana Cooke
Aug 23, 2020·Journal of Clinical Medicine·Koji HatanoNorio Nonomura
Oct 28, 2020·Cells·Daniel J TurnhamHelen B Pearson
Oct 6, 2020·Advances in Biological Regulation·Nilufar RahimovaMarcelo G Kazanietz
Jul 20, 2021·Journal of Medicinal Chemistry·Eleonora ElhalemMaría J Comin
Aug 28, 2021·Cancers·Maeve KielyStefan Ambs
Oct 27, 2021·Clinical and Experimental Pharmacology & Physiology·Zahra BagherianMohammad M Farajollahi

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Methods Mentioned

BETA
nuclear translocation
xenograft
PCR

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