Resveratrol antagonizes EGFR-dependent Erk1/2 activation in human androgen-independent prostate cancer cells with associated isozyme-selective PKC alpha inhibition

Invest New Drugs. 2004 Apr;22(2):107-17. doi: 10.1023/


The development of androgen-independent prostate cancer (AI PrCa) involves constitutive Erk1/2 activation sustained by the epidermal growth factor/transforming growth factor-alpha/EGF receptor (EGF/TGFalpha/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 PKCalpha, epsilon, zeta, iota, and PKD (PKCmicro), 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 PKCalpha to the membrane/cytoskeleton and selectively diminished the amount of autophosphorylated PKCalpha 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 PKCalpha inhibition. The results provide evidence that resveratrol may have value as an adjuvant cancer therapeutic in advanced prostate cancer.

Publication types

  • Comparative Study

MeSH terms

  • Androgens / metabolism
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Cell Survival / physiology
  • Dose-Response Relationship, Drug
  • Enzyme Activation / drug effects
  • Enzyme Activation / physiology
  • Enzyme Inhibitors / pharmacology*
  • ErbB Receptors / metabolism*
  • Humans
  • Isoenzymes / antagonists & inhibitors
  • Isoenzymes / metabolism
  • Male
  • Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
  • Mitogen-Activated Protein Kinase 1 / metabolism*
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases / antagonists & inhibitors
  • Mitogen-Activated Protein Kinases / metabolism*
  • Prostatic Neoplasms / enzymology*
  • Protein Kinase C / antagonists & inhibitors
  • Protein Kinase C / metabolism
  • Protein Kinase C-alpha
  • Resveratrol
  • Stilbenes / pharmacology*


  • Androgens
  • Enzyme Inhibitors
  • Isoenzymes
  • Stilbenes
  • ErbB Receptors
  • PRKCA protein, human
  • Protein Kinase C
  • Protein Kinase C-alpha
  • Mitogen-Activated Protein Kinase 1
  • Mitogen-Activated Protein Kinase 3
  • Mitogen-Activated Protein Kinases
  • Resveratrol