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

We determined whether resveratrol, a phenolic anti-oxidant 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 E-2. 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-alpha, ERK1, and c-Jun led to 4.7-, 5.1-, and C-fold increases in COX-2 promoter activity, respectively. These effects also were inhibited by resveratrol, Resveratrol blocked PMA-dependent activation of AP-l-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.