Journal Article

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

Ki Won Lee, Nam Joo Kang, Evgeny A. Rogozin, Hong-Gyum Kim, Yong Yeon Cho, Ann M. Bode, Hyong Joo Lee, Young-Joon Surh, G. Tim Bowden and Zigang Dong

in Carcinogenesis

Volume 28, issue 9, pages 1918-1927
Published in print September 2007 | ISSN: 0143-3334
Published online August 2007 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgm110
Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1

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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.

Journal Article.  7544 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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