title: Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1.
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 approximately 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 microM) 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 microM). 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.
authors: Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
authors: Ki Won
authors: KW
authors: Lee
authors: Nam Joo
authors: NJ
authors: Kang
authors: Evgeny A
authors: EA
authors: Rogozin
authors: Hong-Gyum
authors: HG
authors: Kim
authors: Yong Yeon
authors: YY
authors: Cho
authors: Ann M
authors: AM
authors: Bode
authors: Hyong Joo
authors: HJ
authors: Lee
authors: Young-Joon
authors: YJ
authors: Surh
authors: G Tim
authors: GT
authors: Bowden
authors: Zigang
authors: Z
authors: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects*; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000494:pharmacology; D048888:Fireflies / Q000201:enzymology; D005419:Flavonoids / Q000494:pharmacology*; D017930:Genes, Reporter; D008156:Luciferases / Q000235:genetics; D048369:MAP Kinase Kinase 1 / Q000037:antagonists & inhibitors* / Q000235:genetics; D051379:Mice; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D005419:Flavonoids; D011994:Recombinant Proteins; D004815:Epidermal Growth Factor; C040015:myricetin; D008156:Luciferases; D048369:MAP Kinase Kinase 1; C482127:Map2k1 protein, mouse; D013755:Tetradecanoylphorbol Acetate