Joydeb Kumar Kundu, Young Kee Shin, Sung Hoon Kim1 and Young-Joon Surh^*

National Research Laboratory of Molecular Carcinogenesis and Chemoprevention, College of Pharmacy, Seoul National University, Seoul 151-742 and 1Graduate School of East-West Medical Science, Kyunghee University, Yongin 449-701, Korea

^*To whom correspondence should be addressed at: College of Pharmacy, Seoul National University, Shillim-dong, Kwanak-ku, Seoul 151-742, Korea.

Abstract
Aberrant expression of cyclooxygenase-2 (COX-2) has been implicated in tumor promotion. Resveratrol, a phytoalexin present in grapes, was reported to inhibit multistage mouse skin carcinogenesis. In the present study, we found that topically applied resveratrol significantly inhibited COX-2 expression induced by the tumor promoter 12-O-tetradecanoylphorbol-13-acetate (TPA). Resveratrol-suppressed phosphorylation and subsequent degradation of IκBα, thereby inhibiting activation of nuclear factor-κB (NF-κB) in TPA-stimulated mouse skin. Pretreatment with resveratrol also suppressed TPA-induced phosphorylation of extracellular signal-regulated protein kinase (ERK) and p38 mitogen-activated protein (MAP) kinase. Resveratrol blunted TPA-induced phosphorylation of p65 and its interaction with CBP/p300, rendering NF-κB transcriptionally inactive. To get further insights into the molecular basis of NF-κB inactivation by resveratrol, we examined the role of IκB kinase (IKK) in mediating TPA-induced activation of NF-κB and COX-2 expression. TPA treatment led to rapid induction of IKK activity in mouse skin, which was abolished either by resveratrol or an IKK inhibitor Bay 11-7082. Topical application of Bay 11-7082 also abrogated TPA-induced NF-κB activation and COX-2 expression, supporting the involvement of IKK in TPA-induced COX-2 expression. Taken together, the above findings suggest that resveratrol targets IKK in blocking TPA-induced NF-κB activation and COX-2 expression in mouse skin in vivo.

Key words : AP-1, activator protein-1 CBP, cyclic AMP-response element binding protein (CREB)-binding protein COX-2, cyclooxygenase-2 ERK, extracellular signal-regulated protein kinase IKK, IκB kinase MAPK, mitogen-activated protein (MAP) kinase NF-κB, nuclear factor-κB SDS, sodium dodecyl sulphate TPA, 12-O-tetradecanoylphorbol-13-acetate