title: Myricetin directly targets JAK1 to inhibit cell transformation.
abstract: JAK1/STAT3 pathway has been suggested to play a role in cell transformation and carcinogenesis. In the present study, we found that myricetin (3, 3', 4', 5, 5', 7-hexahydroxyflavone), a typical flavonol existing in many fruits and vegetables, could directly bind to JAK1/STAT3 molecules to inhibit cell transformation in epidermal growth factor (EGF)-activated mouse JB6 P(+) cells. Colony assay revealed that myricetin had the strongest inhibitory effect on cell transformation among three flavonols including myricetin, quercetin and kaempferol. Molecular data revealed that myricetin inhibited DNA- binding and transcriptional activity of STAT3. Furthermore, myricetin inhibited the phosphorylation of STAT3 at Tyr705 and Ser727. Cellular signaling analyses revealed that EGF could induce the phosphorylation of Janus Kinase (JAK) 1, but not JAK2. Myricetin inhibited the phosphorylation of JAK1 and increased the autophosphorylation of EGF receptor (EGFR). Moreover, ex vivo and in vitro pull-down assay revealed that myricetin bound to JAK1 and STAT3, but not EGFR. Affinity data further demonstrated that myricetin had a higher affinity for JAK1 than STAT3. Thus, our data indicate that myricetin might directly target JAK1 to block cell transformation in mouse JB6 cells.
authors.affiliation: Department of Biochemical Science and Technology, Faculty of Agriculture, Kagoshima University, Korimoto 1-21-24, Kagoshima City 890-0065, Japan.
authors.forename: Takuma
authors.initials: T
authors.lastname: Kumamoto
authors.forename: Makoto
authors.initials: M
authors.lastname: Fujii
authors.forename: De-Xing
authors.initials: DX
authors.lastname: Hou
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D002460:Cell Line; D002471:Cell Transformation, Neoplastic; D004247:DNA / Q000737:chemistry; D004815:Epidermal Growth Factor / Q000378:metabolism; D005419:Flavonoids / Q000378:metabolism* / Q000494:pharmacology; D053613:Janus Kinase 1 / Q000378:metabolism*; D044949:Kaempferols / Q000494:pharmacology; D051379:Mice; D010766:Phosphorylation; D011485:Protein Binding; D011794:Quercetin / Q000494:pharmacology; D050796:STAT3 Transcription Factor / Q000378:metabolism*; D014158:Transcription, Genetic
chemical_list: D000975:Antioxidants; D005419:Flavonoids; D044949:Kaempferols; D050796:STAT3 Transcription Factor; D004815:Epidermal Growth Factor; C006552:kaempferol; C040015:myricetin; D004247:DNA; D011794:Quercetin; D053613:Janus Kinase 1