Myricetin suppresses UVB-induced skin cancer by targeting Fyn

Keun Jung Sung, Won Lee Ki, Sanguine Byun, Joo Kang Nam, Hwan Lim Sung, Yong Seok Heo, Ann M. Bode, G. Tim Bowden, Joo Lee Hyong, Zigang Dong

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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-κB 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]pyrimiidine, 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.

Original languageEnglish
Pages (from-to)6021-6029
Number of pages9
JournalCancer Research
Volume68
Issue number14
DOIs
Publication statusPublished - 2008 Jul 15

All Science Journal Classification (ASJC) codes

  • Oncology
  • Cancer Research

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    Sung, K. J., Ki, W. L., Byun, S., Nam, J. K., Sung, H. L., Heo, Y. S., Bode, A. M., Bowden, G. T., Hyong, J. L., & Dong, Z. (2008). Myricetin suppresses UVB-induced skin cancer by targeting Fyn. Cancer Research, 68(14), 6021-6029. https://doi.org/10.1158/0008-5472.CAN-08-0899