title: Myricetin suppresses UVB-induced skin cancer by targeting Fyn.
abstract: Skin cancer is currently the most common type of human cancer in Americans. Myricetin, a naturally occurring phytochemical, has potent anticancer-promoting activity and contributes to the chemopreventive potential of several foods, including red wine. Here, we show that myricetin suppresses UVB-induced cyclooxygenase-2 (COX-2) expression in mouse skin epidermal JB6 P+ cells. The activation of activator protein-1 and nuclear factor-kappaB induced by UVB was dose-dependently inhibited by myricetin treatment. Western blot and kinase assay data revealed that myricetin inhibited Fyn kinase activity and subsequently attenuated UVB-induced phosphorylation of mitogen-activated protein kinases. Pull-down assays revealed that myricetin competitively bound with ATP to suppress Fyn kinase activity. Importantly, myricetin exerted similar inhibitory effects compared with 4-amino-5-(4-chloro-phenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine, a well-known pharmacologic inhibitor of Fyn. In vivo mouse skin data also revealed that myricetin inhibited Fyn kinase activity directly and subsequently attenuated UVB-induced COX-2 expression. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Docking data suggest that myricetin is easily docked to the ATP-binding site of Fyn, which is located between the N and C lobes of the kinase domain. Overall, these results indicated that myricetin exerts potent chemopreventive activity mainly by targeting Fyn in skin carcinogenesis.
authors.affiliation: Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
authors.forename: Sung Keun
authors.initials: SK
authors.lastname: Jung
authors.forename: Ki Won
authors.initials: KW
authors.lastname: Lee
authors.forename: Sanguine
authors.initials: S
authors.lastname: Byun
authors.forename: Nam Joo
authors.initials: NJ
authors.lastname: Kang
authors.forename: Sung Hwan
authors.initials: SH
authors.lastname: Lim
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Ann M
authors.initials: AM
authors.lastname: Bode
authors.forename: G Tim
authors.initials: GT
authors.lastname: Bowden
authors.forename: Hyong Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Zigang
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005419:Flavonoids / Q000494:pharmacology*; D051379:Mice; D008813:Mice, Inbred ICR; D008954:Models, Biological; D016328:NF-kappa B / Q000378:metabolism; D009381:Neoplasms, Radiation-Induced / Q000188:drug therapy*; D010766:Phosphorylation; D051076:Proto-Oncogene Proteins c-fyn / Q000378:metabolism*; D012878:Skin Neoplasms / Q000188:drug therapy* / Q000209:etiology*; D018808:Transcription Factor AP-1 / Q000378:metabolism; D014466:Ultraviolet Rays
chemical_list: D000970:Antineoplastic Agents; D005419:Flavonoids; D016328:NF-kappa B; D018808:Transcription Factor AP-1; C040015:myricetin; C494960:Fyn protein, mouse; D051076:Proto-Oncogene Proteins c-fyn