Resveratrol inhibits phorbol ester-induced cyclooxygenase-2 expression in mouse skin: MAPKs and AP-1 as potential molecular targets.
Multiple lines of evidence from laboratory studies suggest that resveratrol, a polyphenolic antioxidant present in grapes, has potent chemopreventive activity. Resveratrol has been reported to inhibit chemically-induced carcinogenesis in mouse skin, but the underlying mechanisms remain unclarified. Since an abnormally elevated level of cyclooxygenase-2 (COX-2) has been implicated in carcinogenesis, we investigated the effect of resveratrol on 12-O-tetradecanoylphorbol-13-acetate (TPA)-induced COX-2 expression in mouse skin. Pretreatment of dorsal skin of female ICR mice with resveratrol inhibited TPA-induced COX-2 expression in a dose dependent manner. To elucidate the molecular mechanism underlying COX-2 inhibition by resveratrol, we examined its effect on TPA-induced activation of mitogen-activated protein kinases (MAPK) and transcription factors which regulate COX-2 expression. Resveratrol pretreatment resulted in a decrease in the phosphorylation of extracellular signal-regulated protein kinase (ERK) as well as the catalytic activity of ERK and p38 MAPK. In addition, resveratrol prevented TPA-induced DNA binding of activator protein-1 (AP-1). Taken together, suppression of COX-2 expression by blocking the activation of MAPKs and AP-1 may represent possible molecular mechanisms responsible for previously reported anti-tumor promoting effects of resveratrol on mouse skin carcinogenesis.
Kundu
Joydeb Kumar
JK
College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
Chun
Kyung-Soo
KS
Kim
Sue O
SO
Surh
Young-Joon
YJ
D000818:Animals; D000972:Antineoplastic Agents, Phytogenic / Q000494:pharmacology*; D051546:Cyclooxygenase 2; D005260:Female; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects*; D051379:Mice; D008813:Mice, Inbred ICR; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D011451:Prostaglandin-Endoperoxide Synthases / Q000235:genetics*; D000077185:Resveratrol; D012867:Skin / Q000187:drug effects / Q000201:enzymology*; D013267:Stilbenes / Q000494:pharmacology*; D013755:Tetradecanoylphorbol Acetate / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D000972:Antineoplastic Agents, Phytogenic; D013267:Stilbenes; D018808:Transcription Factor AP-1; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D013755:Tetradecanoylphorbol Acetate; D000077185:Resveratrol