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-alpha, 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.
Highlights
There are two isoforms of cyclooxygenase (COX)1 that catalyze the formation of prostaglandins (PGs) from arachidonic acid
To evaluate whether the inhibition of PG synthesis was because of inhibition of COX-2 or COX-1, we compared the effects of resveratrol and a selective inhibitor of COX-2 (NS398)
As resveratrol (30 M) caused approximately a 70% decrease in basal production of PGE2 (Fig. 2A), our data show that the predominant inhibitory effect of resveratrol on synthesis of PGs was via inhibition of the COX-2 isoform of cyclooxygenase
Summary
There are two isoforms of cyclooxygenase (COX)1 that catalyze the formation of prostaglandins (PGs) from arachidonic acid. 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. PMA caused about a 6-fold increase in COX-2 promoter activity, which was suppressed by resveratrol.
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