Carcinogenesis Advance Access originally published online on August 11, 2007
Carcinogenesis 2007 28(9):1918-1927; doi:10.1093/carcin/bgm110
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Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1
1 Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA
2 Department of Bioscience and Biotechnology and Institute of Biomedical Science & Technology, Konkuk University, Seoul 143-701, Republic of Korea
3 College of Pharmacy
4 School of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea
5 Arizona Cancer Center, The University of Arizona, AZ85724-5024, USA
* To whom correspondence should be addressed. Tel: +507 437 9600; Fax: +507 437 9606; Email: zgdong{at}hi.umn.edu
Evidence suggests that mitogen-activated protein kinase kinase (MEK) plays a role in cell transformation and tumor development and might be a significant target for chemoprevention. 3,5,4'-Trihydroxy-trans-stilbene (resveratrol), a non-flavonoid polyphenol found in various foods and beverages, including red wines, is reported to be a natural chemopreventive agent. However, the concentrations required to exert these effects might be difficult to achieve by drinking only one or two glasses of red wine a day. On the other hand, the flavonol content of red wine is 
30 times higher than that of resveratrol. Here we demonstrated that 3,3',4',5,5',7-hexahydroxyflavone (myricetin), one of the major flavonols in red wine, is a novel inhibitor of MEK1 activity and transformation of JB6 P+ mouse epidermal cells. Myricetin (10 µM) inhibited 12-O-tetradecanoylphorbol-13-acetate (TPA) or epidermal growth factor (EGF)-induced cell transformation by 76 or 72%, respectively, compared with respective reductions of 26 or 19% by resveratrol (20 µM). A combination of myricetin and resveratrol exerted additive but not synergistic effects on either TPA- or EGF-induced transformation. Myricetin, but not resveratrol, attenuated tumor promoter-induced activation of c-fos or activator protein-1. Myricetin strongly inhibited MEK1 kinase activity and suppressed TPA- or EGF-induced phosphorylation of extracellular signal-regulated kinase (ERK) or p90 ribosomal S6 kinase, downstream targets of MEK. Moreover, myricetin inhibited H-Ras-induced cell transformation more effectively than either PD098059, a MEK inhibitor, or resveratrol. Myricetin directly bound with glutathione S-transferase-MEK1 but did not compete with ATP. Overall, these results indicated that myricetin has potent anticancer-promoting activity and mainly targets MEK signaling, which may contribute to the chemopreventive potential of several foods including red wines.
Abbreviations: AP-1, activator protein-1; DTT, dithiothreitol; EDTA, ethylenediamine tetraacetic acid; EGF, epidermal growth factor; FBS, fetal bovine serum; MAP, mitogen-activated protein; MEM, Eagle's minimum essential medium; TPA, 12-O-tetradecanoylphorbol-13-acetate
Received January 5, 2007; revised April 27, 2007; accepted April 27, 2007.