Journal Article

Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-κB in mouse skin by blocking IκB kinase activity

Joydeb Kumar Kundu, Young Kee Shin, Sung Hoon Kim and Young-Joon Surh

in Carcinogenesis

Volume 27, issue 7, pages 1465-1474
Published in print July 2006 | ISSN: 0143-3334
Published online February 2006 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi349
Resveratrol inhibits phorbol ester-induced expression of COX-2 and activation of NF-κB in mouse skin by blocking IκB kinase activity

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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.

Keywords: 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

Journal Article.  6884 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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