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Resveratrol inhibits phorbol ester and UV-induced activator protein 1 activation by interfering with
1Department of Pharmaceutics and Pharmacodynamics, Center for Pharmaceutical Biotechnology, College of Pharmacy, University of Illinois at Chicago, Chicago, Illinois, USA.
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.
Insights
Resveratrol inhibits cancer-promoting activator protein 1 (AP-1) and mitogen-activated protein kinase (MAPK) pathways. This chemopreventive effect may stem from resveratrol
Area of Science:
- Molecular Biology
- Biochemistry
- Cancer Research
Background:
- Resveratrol, a natural phenolic compound, exhibits chemopreventive properties against chemical-induced carcinogenesis in animal models.
- Activator protein 1 (AP-1) is a critical transcription factor implicated in carcinogenesis and tumor transformation.
- Understanding resveratrol's mechanism against cancer requires investigating its effects on key signaling pathways like AP-1.
Purpose of the Study:
- To elucidate the chemopreventive mechanism of resveratrol by examining its effects on Activator protein 1 (AP-1) activity.
- To investigate resveratrol's impact on mitogen-activated protein kinase (MAPK) pathways, which are crucial for AP-1 activation.
- To identify the specific molecular targets of resveratrol within the AP-1 and MAPK signaling cascades.
Main Methods:
- HeLa cells were pretreated with resveratrol and then stimulated with ultraviolet C (UVC) or phorbol 12-myristate 13-acetate (PMA).
- AP-1 reporter gene transcription and the activation of ERK2, JNK1, and p38 kinases were measured.
- The study utilized dominant-negative mutants of kinases, isolated protein kinases, and selective kinase inhibitors to probe signaling pathways.
Main Results:
- Resveratrol pretreatment significantly inhibited UVC- and PMA-induced AP-1 reporter gene transcription.
- Resveratrol suppressed the activation of extracellular signal-regulated protein kinase 2 (ERK2), c-jun N-terminal kinase 1 (JNK1), and p38.
- Resveratrol diminished the kinase activities of c-Src protein tyrosine kinase and protein kinase C, suggesting these as potential targets.
Conclusions:
- Resveratrol exerts chemopreventive effects by inhibiting AP-1 and MAPK signaling pathways.
- The mechanism involves the suppression of protein tyrosine kinases and protein kinase C activities.
- These findings provide molecular insights into how resveratrol may prevent cancer development.