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Resveratrol Antagonizes EGFR-Dependent Erk1/2 Activation in Human Androgen-Independent Prostate Cancer Cells with Associated Isozyme-Selective PKCα Inhibition

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Abstract

The development of androgen-independent prostate cancer (AI PrCa) involves constitutive Erk1/2 activation sustained by the epidermal growth factor/transforming growth factor-α/EGF receptor (EGF/TGFα/EGFR) axis and other trophic signaling mechanisms in neoplastic human prostate epithelial cells in vivo. In this report, we show that growth-inhibitory concentrations of the dietary phytochemical resveratrol suppress EGFR-dependent Erk1/2 activation pathways stimulated by EGF and phorbol ester (12-O-tetradecanoyl phorbol 13-acetate, TPA) in human AI PrCa PC-3 cells in vitro. Because protein kinase C (PKC) is the major cellular receptor for phorbol esters and taking into consideration that resveratrol is PKC-inhibitory, we investigated resveratrol effects on cellular PKC isozymes associated with the suppression of TPA-induced Erk1/2 activation. The PKC isozyme composition of PC-3 cells was defined by Western analysis of the cell lysate with a comprehensive set of isozyme-selective PKC Ab's. PC-3 cells expressed PKCα, ε, ζ, ι, and PKD (PKCμ), as did another human AI PrCa cell line of distinct genetic origin, DU145. The effects of resveratrol on TPA-induced PKC isozyme activation were defined by monitoring PKC isozyme translocation and autophosphorylation. Under conditions where resveratrol suppressed TPA-induced Erk1/2 activation, the phytochemical produced isozyme-selective interference with TPA-induced translocation of cytosolic PKCα to the membrane/cytoskeleton and selectively diminished the amount of autophosphorylated PKCα in the membrane/cytoskeleton of the TPA-treated cells. These results demonstrate that resveratrol abrogation of a PKC-mediated Erk1/2 activation response in PC-3 cells correlates with isozyme-selective PKCα inhibition. The results provide evidence that resveratrol may have value as an adjuvant cancer therapeutic in advanced prostate cancer.

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  1. Department of Cancer Biology, U.T.M.D. Anderson Cancer Center, Houston, TX, 77030, U.S.A

    Jubilee R. Stewart & Catherine A. O'Brian

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Stewart, J.R., O'Brian, C.A. Resveratrol Antagonizes EGFR-Dependent Erk1/2 Activation in Human Androgen-Independent Prostate Cancer Cells with Associated Isozyme-Selective PKCα Inhibition. Invest New Drugs 22, 107–117 (2004). https://doi.org/10.1023/B:DRUG.0000011787.75522.ec

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  • DOI: https://doi.org/10.1023/B:DRUG.0000011787.75522.ec

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