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

Oncogene volume 37, pages 4735–4749 (2018)Cite this article

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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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Acknowledgements

This work was supported by grants R01-CA089202, R01-CA189765, R01-CA196232 (NIH), and PC130641 (DOD) to M.G.K., and W81XWH-12-1-0009 (DOD) to R.G. This study made use of the Research Animal Support Facility at MD Anderson Cancer Center, Smithville, including Laboratory Animal Genetic Services and Mutant Mouse Pathology Services, which are supported by DHHS/NCI Cancer Center Support grant P30 CA016672.

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  1. Department of Systems Pharmacology and Translational Therapeutics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Rachana Garg, Emer M. Smyth, Emanuela Ricciotti, Tilo Grosser & Marcelo G. Kazanietz

  2. Department of Immunology, Immunopathology Laboratory, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA

    Jorge M. Blando

  3. Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Smithville, TX, 78957, USA

    Carlos J. Perez & Fernando Benavides

  4. The University of Texas Graduate School of Biomedical Sciences, Houston, TX, 77030, USA

    Carlos J. Perez & Fernando Benavides

  5. Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, 19104, USA

    Priti Lal & Michael D. Feldman

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  1. Rachana Garg
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Garg, R., Blando, J.M., Perez, C.J. et al. COX-2 mediates pro-tumorigenic effects of PKCε in prostate cancer. Oncogene 37, 4735–4749 (2018). https://doi.org/10.1038/s41388-018-0318-9

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