Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with mitogen-activated protein kinase pathways

Resveratrol, a phenolic compound found in grapes and other food products, p revents chemical-induced carcinogenesis in a number of animal models of can cers. To better understand its chemopreventive property, we examined effect s of resveratrol on the activity of activator protein 1 (AP-1), a dimeric t ranscription factor that plays a critical role in the carcinogenesis and tu mor transformation. Pretreatment of HeLa cells with resveratrol inhibited t he transcription of AP-1 reporter gene by UVC and phorbol 12-myristate 13-a cetate (PMA). Pretreatment with resveratrol also inhibited the activation o f extracellular signal-regulated protein kinase 2 (ERK2), c-jun N-terminal kinase 1 (JNK1), and p38. Selectively blocking mitogen-activated protein ki nase (MAPK) pathways by overexpression of dominant-negative mutants of kina ses attenuated the AP-1 activation by PMA and UVC. Interestingly, resveratr ol 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 t he signaling molecules upstream of Raf-1 or MEKK1. Indeed, incubation of re sveratrol with the isolated c-Src protein tyrosine kinase and protein kinas e C diminished their kinase activities. Furthermore, inhibition of protein tyrosine kinases and protein kinase C with their selective inhibitors impai red the activation of MAPKs as well as the induction of AP-1 activity by PM A and UVC. In addition, modulation of estrogen receptor activity with 17 be ta -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 an d MAPK pathways may involve the inhibition of both protein tyrosine kinases and protein kinase C.