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Myricetin Suppresses UVB-Induced Skin Cancer by Targeting Fyn

¹ Department of Agricultural Biotechnology, Seoul National University; ² Department of Bioscience and Biotechnology and ³ Department of Chemistry, Konkuk University, Seoul, Republic of Korea; ⁴ The Hormel Institute, University of Minnesota, Austin, Minnesota; and ⁵ University of Arizona Cancer Center, Tucson, Arizona

Requests for reprints: Hyong Joo Lee, Department of Agricultural Biotechnology, Seoul National University, Seoul 151-742, Republic of Korea. Phone: 82-2-880-4860; Fax: 82-2-873-5095; E-mail: leehyjo{at}snu.ac.kr or Zigang Dong, Hormel Institute, University of Minnesota, 801 16th Avenue NE, Austin, MN 55912. Phone: 507-437-9600; Fax: 507-437-9606; E-mail: zgdong{at}hi.umn.edu.

Key Words: Fyn • myricetin • skin cancer

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-B 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. [Cancer Res 2008;68(14):6021–9]