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Integrin signaling links protein kinase Cɛ to the protein kinase B/Akt survival pathway in recurrent prostate cancer cells

Oncogene volume 23, pages 8659–8672 (2004)Cite this article

Abstract

Failure of hormone therapy often involves an outgrowth of protein kinase Cɛ (PKCɛ)-positive cells in recurrent prostate cancer. Our previous investigations have uncovered evidence of a complex signaling network operating downstream of this oncogenic protein kinase to actively advance the survival and proliferation of prostate cancer cells. In this study, we present evidence of a functional interplay among integrin receptors, PKCɛ, and protein kinase B (PKB/Akt) in recurrent CWR-R1 prostate cancer cells. Flow cytometry and confocal microscopy provided evidence that PKCɛ signaling promoted the assembly of matrix adhesions containing an abundance of colocalized actin filaments and β1 integrins that exhibited an exposed activation epitope on the surface of live CWR-R1 cells. Reciprocal coimmunoprecipitations provided evidence of signaling complexes containing PKCɛ, β1 integrins, Src, and PKB/Akt in CWR-R1 cell cultures. An investigation into the functional significance of these interactions, and of their positive influence on β1 integrins, demonstrated that PKCɛ and several key components of the PKB/Akt signaling pathway remain constitutively phosphorylated/activated in adherent but not suspension cultures of PTEN-positive CWR-R1 cells. Gene transfer, antisense and pharmacological experiments provided additional support for the hypothesis that a mutually reinforcing signaling loop sustains the activation of β1 integrins, PKCɛ, and PKB/Akt in adherent prostate cancer cells.

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Acknowledgements

We gratefully acknowledge Dr Christopher W Gregory (Voyager Pharmaceutical Corp., Raleigh, NC) for providing CWR22 tumor lysates. National Institutes of Health Grant (R01 CA98195 to JAM) and the DOD Prostate Cancer Research Program (DAMD 17-02-1-0053 to DMT) supported this work.

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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

    Daqing Wu, Chittam U Thakore, Ginger G Wescott & David M Terrian

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

    James A McCubrey

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

    James A McCubrey & David M Terrian

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  1. Daqing Wu
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Correspondence to David M Terrian.

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Wu, D., Thakore, C., Wescott, G. et al. Integrin signaling links protein kinase Cɛ to the protein kinase B/Akt survival pathway in recurrent prostate cancer cells. Oncogene 23, 8659–8672 (2004). https://doi.org/10.1038/sj.onc.1207900

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