title: Quercetin-3-methyl ether suppresses proliferation of mouse epidermal JB6 P+ cells by targeting ERKs.
abstract: Chemoprevention has been acknowledged as an important and practical strategy for the management of skin cancer. Quercetin-3-methyl ether, a naturally occurring compound present in various plants, has potent anticancer-promoting activity. We identified this compound by in silico virtual screening of the Traditional Chinese Medicine Database using extracellular signal-regulated kinase 2 (ERK2) as the target protein. Here, we showed that quercetin-3-methyl ether inhibited proliferation of mouse skin epidermal JB6 P+ cells in a dose- and time-dependent manner by inducing cell cycle G(2)-M phase accumulation. It also suppressed 12-O-tetradecanoylphorbol-13-acetate-induced neoplastic cell transformation in a dose-dependent manner. Its inhibitory effect was greater than quercetin. The activation of activator protein-1 was dose-dependently suppressed by quercetin-3-methyl ether treatment. Western blot and kinase assay data revealed that quercetin-3-methyl ether inhibited ERKs kinase activity and attenuated phosphorylation of ERKs. Pull-down assays revealed that quercetin-3-methyl ether directly binds with ERKs. Furthermore, a loss-of-function ERK2 mutation inhibited the effectiveness of the quercetin-3-methyl ether. Overall, these results indicated that quercetin-3-methyl ether exerts potent chemopreventive activity by targeting ERKs.
authors.affiliation: The Hormel Institute, University of Minnesota, Austin, MN 55912, USA.
authors.forename: Jixia
authors.initials: J
authors.lastname: Li
authors.forename: Madhusoodanan
authors.initials: M
authors.lastname: Mottamal
authors.forename: Haitao
authors.initials: H
authors.lastname: Li
authors.forename: Kangdong
authors.initials: K
authors.lastname: Liu
authors.forename: Feng
authors.initials: F
authors.lastname: Zhu
authors.forename: Yong-Yeon
authors.initials: YY
authors.lastname: Cho
authors.forename: Carlos P
authors.initials: CP
authors.lastname: Sosa
authors.forename: Keyuan
authors.initials: K
authors.lastname: Zhou
authors.forename: G Tim
authors.initials: GT
authors.lastname: Bowden
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D002453:Cell Cycle / Q000187:drug effects; D059447:Cell Cycle Checkpoints / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects; D002478:Cells, Cultured; D018890:Chemoprevention / Q000379:methods; D000078404:Epidermal Cells; D004817:Epidermis / Q000187:drug effects* / Q000201:enzymology / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D008516:Medicine, Chinese Traditional / Q000379:methods; D051379:Mice; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism*; D009154:Mutation; D010766:Phosphorylation / Q000187:drug effects; D011794:Quercetin / Q000031:analogs & derivatives; D012878:Skin Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000517:prevention & control; D018808:Transcription Factor AP-1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation / Q000187:drug effects
chemical_list: D005419:Flavonoids; D018808:Transcription Factor AP-1; C459210:quercetin 3-O-methyl ether; D011794:Quercetin; D048052:Mitogen-Activated Protein Kinase 3