Resveratrol Inhibits Cyclooxygenase-2 Transcription and Activity in Phorbol Ester-treated Human Mammary Epithelial Cells

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 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-␣, 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.

The antioxidant resveratrol protects against chondrocyte apoptosis via effects on mitochondrial polarization and ATP production

“…Its effects were mediated at the level of COX-2, by suppression of COX-2 gene expression and direct inhibition of COX activity, without effects on either of the PGE 2 synthases (cPGES and mPGES). Similar findings have been reported in human mammary epithelial cells, in which resveratrol inhibited phorbol myristate acetate (PMA)-induced PGE 2 production by blocking transcription and COX enzyme function (32). Studies investigating resveratrol-mediated inhibition of COX in other cell types have demonstrated inhibition of peroxidase function, with no effect on COX enzyme activity (33,34).…”

Inhibition of cyclo-oxygenase 2 expression in colon cells by the chemopreventive agent curcumin involves inhibition of NF-κB activation via the NIK/IKK signalling complex

“…A similar mechanism may be operated by PMA (Ghosh and Baltimore, 1990). Both TNF and fecapentaene-12 activate AP1 (Zeng-gang et al, 1996;Holloway et al, 1998), which is important in the induction of COX2 transcription by v-Src (Xie and Herschman, 1995) and PMA (Subbaramaiah et al, 1998). Since curcumin inhibits AP1 dependent transactivation (Huang et al, 1991), some of the inhibitory e ects of curcumin on COX2 gene induction by the tumour promoters may also be mediated by inhibition of AP-1 (Kelley et al, 1996).…”

Dietary and other risk factors in women having fibrocystic breast conditions with and without concurrent breast cancer: A nested case‐control study in Shanghai, China

“…Several reports have demonstrated that resveratrol, a natural phytoalexin found in high concentrations in grape skin, has strong anti-carcinogenetic effects in in vitro systems and animal models. 40,41 Multiple potential mechanisms involving initiation, promotion and progression have been identified. 42,43 Although our observations support an antineoplastic role of resveratrol as reported by Savouret et al, 44 grape intake even among the highest quartiles was very low.…”