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COX-2 mediates pro-tumorigenic effects of PKC? in prostate cancer.


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

SUBMITTER: Garg R 

PROVIDER: S-EPMC6195867 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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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  ...[more]

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