Resveratrol inhibits cyclooxygenase-2 transcription and activity in phorbol ester-treated human mammary epithelial cells

Kotha Subbaramaiah, Wen Jing Chung, Pedro Michaluart, Nitin Telang, Tadashi Tanabe, Hiroyasu Inoue, Meishiang Jang, John M. Pezzuto, Andrew J. Dannenberg

Research output: Contribution to journalArticle

715 Scopus citations

Abstract

We determined whether resveratrol, a phenolic antioxidant found in grapes and other food products, inhibited phorbol ester (PMA)-mediated induction of COX-2 in human mammary and oral epithelial cells. Treatment of cells with PMA induces COX-2 and causes a marked increase in the production of prostaglandin E2. These effects were inhibited by resveratrol. Resveratrol suppressed PMA-mediated increases in COX-2 mRNA and protein. Nuclear run-offs revealed increased rates of COX-2 transcription after treatment with PMA, an effect that was inhibited by resveratrol. PMA caused about a 6-fold increase in COX-2 promoter activity, which was suppressed by resveratrol. Transient transfections utilizing COX-2 promoter deletion constructs and COX-2 promoter constructs, in which specific enhancer elements were mutagenized, indicated that the effects of PMA and resveratrol were mediated via a cyclic AMP response element. Resveratrol inhibited PMA- mediated activation of protein kinase C. Overexpressing protein kinase C-α, ERK1, and c-Jun led to 4.7-, 5.1-, and 4-fold increases in COX-2 promoter activity, respectively. These effects also were inhibited by resveratrol. Resveratrol blocked PMA-dependent activation of AP-1-mediated gene expression. In addition to the above effects on gene expression, we found that resveratrol also directly inhibited the activity of COX-2. These data are likely to be important for understanding the anti-cancer and anti- inflammatory properties of resveratrol.

Original languageEnglish (US)
Pages (from-to)21875-21882
Number of pages8
JournalJournal of Biological Chemistry
Volume273
Issue number34
DOIs
StatePublished - Aug 21 1998

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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