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

Carcinogenesis. 2006 Jul;27(7):1465-74. doi: 10.1093/carcin/bgi349. Epub 2006 Feb 12.


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 IkappaBalpha, thereby inhibiting activation of nuclear factor-kappaB (NF-kappaB) 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-kappaB transcriptionally inactive. To get further insights into the molecular basis of NF-kappaB inactivation by resveratrol, we examined the role of IkappaB kinase (IKK) in mediating TPA-induced activation of NF-kappaB 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-kappaB 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-kappaB activation and COX-2 expression in mouse skin in vivo.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antineoplastic Agents, Phytogenic / pharmacology*
  • Blotting, Western
  • Carcinogens / pharmacology
  • Cyclooxygenase 2 / biosynthesis*
  • Electrophoretic Mobility Shift Assay
  • Enzyme Activation / drug effects
  • Extracellular Signal-Regulated MAP Kinases / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Female
  • I-kappa B Kinase / drug effects*
  • I-kappa B Kinase / metabolism
  • Immunohistochemistry
  • Immunoprecipitation
  • Mice
  • Mice, Inbred ICR
  • NF-kappa B / drug effects*
  • NF-kappa B / metabolism
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Resveratrol
  • Skin / drug effects*
  • Skin / metabolism
  • Stilbenes / pharmacology*
  • Sulfones / pharmacology
  • Tetradecanoylphorbol Acetate / pharmacology
  • Transcriptional Activation / drug effects
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • 3-(4-methylphenylsulfonyl)-2-propenenitrile
  • Antineoplastic Agents, Phytogenic
  • Carcinogens
  • NF-kappa B
  • Nitriles
  • Stilbenes
  • Sulfones
  • Cyclooxygenase 2
  • I-kappa B Kinase
  • Extracellular Signal-Regulated MAP Kinases
  • p38 Mitogen-Activated Protein Kinases
  • Tetradecanoylphorbol Acetate
  • Resveratrol