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Vol. 60, Issue 1, 217-224, July 2001

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

Rong Yu, Vidya Hebbar, Daniel W. Kim, Sandhya Mandlekar, John M. Pezzuto, and Ah-Ng Tony Kong

Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology (R.Y., V.H., A.-N.T.K.) and Department of Medicinal Chemistry and Pharmacognosy (J.M.P.), College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois; Abbott Laboratories, North Chicago, Illinois (D.W.K.); and Department of Drug Metabolism, DuPont Pharmaceutics Company, Newark, Delaware (S.M.)

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.

Copyright © 2001 by The American Society for Pharmacology and Experimental Therapeutics


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