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Protein kinase Cɛ interacts with Bax and promotes survival of human prostate cancer cells

Oncogene volume 22, pages 7958–7968 (2003)Cite this article

Abstract

Prostatic glandular epithelial cells express protein kinase Cɛ (PKCɛ), an oncoprotein that coordinately disrupts the reactivation of the tumor suppressor Rb, derepressess transcriptional elongation of the c-myc oncogene, and propagates survival signals in LNCaP cells. Since the activation of such a program may contribute to the progression of human prostate cancer, a proteomic analysis was performed to gain a more global perspective on the signaling network that PKCɛ might be capable of engaging in prostate cancer cells. Using CWR22 xenografts, we identified at least 18 different structural, signaling, and stress-related proteins that associated with PKCɛ, including an interaction with the proapoptotic protein Bax that was novel to recurrent CWR22 tumors. An investigation into the biological significance of the PKCɛ association with Bax provided the first evidence of an inverse relationship between endogenous levels of PKCɛ and susceptibility of prostate cancer cells to the apoptotic effects of phorbol esters. Western blot and antisense experiments demonstrated that CWR-R1 cells expressed moderate levels of PKCɛ and relied on this protein to survive in the presence of phorbol esters, while the apoptosis normally induced by phorbol esters in PKCɛ-deficient LNCaP cells was dependent on the presence of Bax. Forced expression of PKCɛ in LNCaP cells was sufficient to confer a significant resistance to phorbol esters and this resistance was associated with an inhibition of phorbol ester-induced Bax conformational rearrangements that are important for Bax oligomerization, mitochondrial integration, and cytochrome c release. Considered in their entirety, our data suggest that an association of PKCɛ with Bax may neutralize apoptotic signals propagated through a mitochondrial death-signaling pathway.

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Acknowledgements

We gratefully acknowledge Dr Stephanie M Oberhaus (Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University) for her assistance in performing our initial assays of apoptosis. This work was supported by National Institutes of Health Grants ES8397 (to DMT), P01 CA77739 (to JLM), and U54 HD35041 (Tissue Culture Core), and the DOD Prostate Cancer Research Program (DAMD17-02-1-0110 to CWG and DAMD 17-02-1-0053 to DMT).

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Authors and Affiliations

  1. Department of Anatomy and Cell Biology, Brody School of Medicine, East Carolina University, Greenville, 27858, NC, USA

    Meagan A McJilton, C Van Sikes, Ginger G Wescott, Daqing Wu, Tonia L Foreman & David M Terrian

  2. Department of Pathology and Laboratory Medicine, The University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    Christopher W Gregory & James L Mohler

  3. Department of Microbiology and Immunology, Brody School of Medicine, East Carolina University, Greenville, 27858, NC, USA

    Douglas A Weidner

  4. Department of Surgery (Division of Urology), The University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    O Harris Ford, A Morgan Lasater & James L Mohler

  5. UNC-Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill, Chapel Hill, 27599, NC, USA

    O Harris Ford & James L Mohler

  6. Leo W. Jenkins Cancer Center, Brody School of Medicine, East Carolina University, Greenville, 27858, NC, USA

    David M Terrian

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  1. Meagan A McJilton
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Correspondence to David M Terrian.

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McJilton, M., Van Sikes, C., Wescott, G. et al. Protein kinase Cɛ interacts with Bax and promotes survival of human prostate cancer cells. Oncogene 22, 7958–7968 (2003). https://doi.org/10.1038/sj.onc.1206795

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