Myricetin is a novel natural inhibitor of neoplastic cell transformation and MEK1.
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.
Lee
Ki Won
KW
Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912, USA.
Kang
Nam Joo
NJ
Rogozin
Evgeny A
EA
Kim
Hong-Gyum
HG
Cho
Yong Yeon
YY
Bode
Ann M
AM
Lee
Hyong Joo
HJ
Surh
Young-Joon
YJ
Bowden
G Tim
GT
Dong
Zigang
Z
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
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