Investigational New Drugs

, Volume 22, Issue 2, pp 107–117

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

  • Jubilee R. Stewart
  • Catherine A. O'Brian
Article

DOI: 10.1023/B:DRUG.0000011787.75522.ec

Cite this article as:
Stewart, J.R. & O'Brian, C.A. Invest New Drugs (2004) 22: 107. doi:10.1023/B:DRUG.0000011787.75522.ec

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.

resveratrolprotein kinase C-alpha (PKCα)Erk1/2androgen-independent prostate cancerepidermal growth factor receptor

Copyright information

© Kluwer Academic Publishers 2004

Authors and Affiliations

  • Jubilee R. Stewart
    • 1
  • Catherine A. O'Brian
    • 1
  1. 1.Department of Cancer BiologyU.T.M.D. Anderson Cancer CenterHoustonU.S.A