Resveratrol Inhibits Phorbol Ester and UV-Induced Activator Protein 1 Activation by Interfering with Mitogen-Activated Protein Kinase Pathways

Abstract

Resveratrol, a phenolic compound found in grapes and other food products, prevents chemical-induced carcinogenesis in a number of animal models of cancers. To better understand its chemopreventive property, we examined effects of resveratrol on the activity of activator protein 1 (AP-1), a dimeric transcription factor that plays a critical role in the carcinogenesis and tumor transformation. Pretreatment of HeLa cells with resveratrol inhibited the transcription of AP-1 reporter gene by UVC and phorbol 12-myristate 13-acetate (PMA). Pretreatment with resveratrol also inhibited the activation of extracellular signal-regulated protein kinase 2 (ERK2), c-jun N-terminal kinase 1 (JNK1), and p38. Selectively blocking mitogen-activated protein kinase (MAPK) pathways by overexpression of dominant-negative mutants of kinases attenuated the AP-1 activation by PMA and UVC. Interestingly, resveratrol had little effect on the induction of AP-1 reporter gene by active Raf-1, MEKK1, or MKK6, suggesting that it inhibited MAPK pathways by targeting the signaling molecules upstream of Raf-1 or MEKK1. Indeed, incubation of resveratrol with the isolated c-Src protein tyrosine kinase and protein kinase C diminished their kinase activities. Furthermore, inhibition of protein tyrosine kinases and protein kinase C with their selective inhibitors impaired the activation of MAPKs as well as the induction of AP-1 activity by PMA and UVC. In addition, modulation of estrogen receptor activity with 17beta-estradiol had no effect on the inhibition of AP-1 by resveratrol. Taken together, these results suggest that the effects of resveratrol on AP-1 and MAPK pathways may involve the inhibition of both protein tyrosine kinases and protein kinase C.

The early expressed HIV-1 genes regulate DNMT1 expression

“…27,56 For example, the natural product Resveratrol inhibits AP-1 and NFκB activity and the subsequent activation of their target genes. [57][58][59][60] We have shown that the HIV-1 induced changes in DNMT1 expression 22,30 (Fig. 1) are most likely mediated through the transcription factor AP-1 (Fig.…”

The roles of polyphenols in cancer chemoprevention

“…Besides inhibiting the catalytic activity of COX-2, the compound also blocks TPA-mediated induction of COX-2 mRNA in cultured human mammary epithelial cells through repression of AP-1-dependent transactivation [108]. It also inhibits AP-1-, ERK1-, and protein kinase C (PKC)-mediated induction of COX-2 promoter activity [128]. A recent study demonstrated that topically applied resveratrol inhibits TPA-induced COX-2 expression in female ICR mouse skin, further supporting its antitumor-promoting potential [55].…”

New insights on the anticancer properties of dietary polyphenols

“…26 In most cancer cell lines, AP-1 is highly activated, and polyphenols (theaflavin, EGCG, and resveratrol) were described to inhibit the transcriptional activity of AP-1 by TNF-a, PMA, and UV radiation. [27][28][29] In addition, the mechanism behind this decreased activity seems to be the blockade of the ERK2, JNK-1, and p38 MAPK activation, 27 which are the upstream kinases that regulate activation of both NF-kB and AP-1. 24 …”