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

被引:112
作者
Yu, R
Hebbar, V
Kim, DW
Mandlekar, S
Pezzuto, JM
Kong, ANT
机构
[1] Univ Illinois, Coll Pharm, Ctr Pharmaceut Biotechnol, Dept Pharmaceut & Phamacodynam, Chicago, IL USA
[2] Univ Illinois, Coll Pharm, Dept Med Chem & Pharmacognosy, Chicago, IL USA
[3] Abbott Labs, N Chicago, IL 60064 USA
[4] DuPont Pharmaceut Co, Dept Drug Metab, Newark, DE USA
关键词
D O I
10.1124/mol.60.1.217
中图分类号
R9 [药学];
学科分类号
1007 ;
摘要
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 17 beta -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.
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页码:217 / 224
页数:8
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