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

• Published in: Molecular cancer therapeutics 2004-11, Vol.3 (11), p.1355-1364
• Main Authors: Shih, Ai, Zhang, Shenli, Cao, H James, Boswell, Sarah, Wu, Yun-Hsuan, Tang, Heng-Yuan, Lennartz, Michelle R, Davis, Faith B, Davis, Paul J, Lin, Hung-Yun
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Cell Line, Tumor; Enzyme Activation - drug effects; Epidermal Growth Factor - pharmacology; Gene Expression Regulation, Neoplastic; Humans; Male; Prostatic Neoplasms - metabolism; Prostatic Neoplasms - pathology; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; Protein Kinase C-alpha; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins c-fos - metabolism; Proto-Oncogene Proteins c-jun - metabolism; Signal Transduction - drug effects; Stilbenes - antagonists & inhibitors; Stilbenes - pharmacology; Tumor Suppressor Protein p53 - metabolism
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.1355.3.11

Resveratrol, a naturally occurring stilbene with antitumor properties, caused mitogen-activated protein kinase [MAPK, extracellular signal-regulated kinase 1/2 (ERK1/2)] 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 ERK1/2 phosphorylation without significantly altering p53 phosphorylation by resveratrol. DU145 cells transfected with a dominant-negative PKC-α construct showed resveratrol-induced ERK1/2 phosphorylation and Ser 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.