Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1

Ki Won Lee, Nam Joo Kang, Evgeny A. Rogozin, HONGGYUM KIM, Yong Yeon Cho, Ann M. Bode, Hyong Joo Lee, Young Joon Surh, G. Tim Bowden, Zigang Dong

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89 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1918-1927
Number of pages10
JournalCarcinogenesis
Volume28
Issue number9
DOIs
StatePublished - Sep 1 2007

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    Lee, K. W., Kang, N. J., Rogozin, E. A., KIM, HONGGYUM., Cho, Y. Y., Bode, A. M., Lee, H. J., Surh, Y. J., Bowden, G. T., & Dong, Z. (2007). Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1. Carcinogenesis, 28(9), 1918-1927. https://doi.org/10.1093/carcin/bgm110