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.
Bibliographical noteFunding Information:
Hormel Foundation, BioGreeen21 program, Rural Development Administration (nos. 20070301-034-027 and 20070301-034-042), Republic of Korea, National Institutes of Health [CA27502 (note: Chemoprevention of Skin Cancer, Alberts/Bowden) CA120388, CA111536, CA88961, CA81064 to Z.D.]; National Research Laboratory, Ministry of Science and Technology (no. B050007), Republic of Korea to Y.-J.S. Postdoctoral fellowship for K.W.L. from the Korea Science and Engineering Foundation.