Inhibitory effect of epidermal growth factor on resveratrol-induced apoptosis in prostate cancer cells is mediated by protien kinase C-α

Ai Shih, Shenli Zhang, H. James Cao, Sarah Boswell, Yun Hsuan Wu, Heng Yuan Tang, Michelle R. Lennartz, Faith B. Davis, Paul J. Davis, Hung Yun Lin

Research output: Contribution to journalArticlepeer-review

76 Citations (Scopus)


Resveratrol, a naturally occurring stilbene with antitumor properties, caused mitogen-activated protein kinase [MAPK, extracellular signal-regulated kinase 1/2 (ERK 1/2)] activation, nuclear translocation of Ser 15-phosphorylated p53, and p53-dependent apoptosis in hormone-insensitive DU145 prostate cancer cells. Exposure of these cells to epidermal growth factor (EGF) for up to 4 hours resulted in brief activation of MAPK followed by inhibition of resveratrol-induced signal transduction, p53 phosphorylation, and apoptosis. Resveratrol stimulated c-fos and c-jun expression in DU145 cells, an effect also suppressed by EGF. An inhibitor of protein kinase C (PKC)-α, -β, and -γ (CGP41251) enhanced Ser 15 phosphorylation of p53 by resveratrol in the absence of EGF and blocked EGF inhibition of the resveratrol effect. EGF caused PKC-α/β phosphorylation in DU145 cells, an effect reversed by CGP41251. Activation of PKC by phorbol ester (phorbol 12-myristate 13-acetate) enhanced EGF action on ERK 1/2 phosphorylation without significantly altering p53 phosphorylation by resveratrol. DU145 cells transfected with a dominant-negative PKC-α construct showed resveratrol-induced ERK 1/2 phosphorylation and Seri 15 phosphorylation of p53 but were unresponsive to EGF. Thus, resveratrol and EGF activate MAPK by discrete mechanisms in DU145 cells. The stilbene promoted p53-dependent apoptosis, whereas EGF opposed induction of apoptosis by resveratrol via a PKC-α-mediated mechanism. Resveratrol also induced p53 phosphorylation in LNCaP prostate cancer cells, an effect also inhibited by EGF. Inhibition of PKC activation in LNCaP cells, however, resulted in a reduction, rather than increase, in p53 activation and apoptosis, suggesting that resveratrol-induced apoptosis in these two cell lines occurs through different PKC-mediated and MAPK-dependent pathways.

Original languageEnglish
Pages (from-to)1355-1363
Number of pages9
JournalMolecular Cancer Therapeutics
Issue number11
Publication statusPublished - Nov 2004
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Drug Discovery
  • Pharmacology


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