Myricetin suppresses UVB-induced skin cancer by targeting Fyn.
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.
Jung
Sung Keun
SK
Department of Agricultural Biotechnology, Seoul National University, Seoul, Republic of Korea.
Lee
Ki Won
KW
Byun
Sanguine
S
Kang
Nam Joo
NJ
Lim
Sung Hwan
SH
Heo
Yong-Seok
YS
Bode
Ann M
AM
Bowden
G Tim
GT
Lee
Hyong Joo
HJ
Dong
Zigang
Z
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
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