Abstract
Abstract Chronic exposure to solar ultraviolet is a major cause of photoaging and skin carcinogenesis. In the present study, we investigated the effect of myricetin on UVB-induced photoaging, skin cancer, and angiogenesis in JB6 P+ cells and a mouse skin tumorigenesis model. Myricetin inhibited wrinkle formation induced by UVB irradiation (0.18 J/cm2, 3 days/week for 15 weeks) in mouse skin. Myricetin treatment reduced UVB-induced epidermal thickening of mouse skin and also suppressed UVB-induced matrix metalloproteinase-9 (MMP-9) protein expression and enzyme activity. In vitro and in vivo pull-down and kinase assays revealed that myricetin suppressed Raf activity by binding with Raf. Secondly, myricetin suppressed UVB-induced COX-2 expression and mitogen-activated protein kinases in JB6 P+ cells and mouse skin. Pull-down and kinase assay results showed that myricetin directly inhibited UVB-induced Fyn kinase activity by binding with Fyn in an ATP-competitive manner. Mouse skin tumorigenesis data clearly showed that pretreatment with myricetin significantly suppressed UVB-induced skin tumor incidence in a dose-dependent manner. Topical treatment with myricetin suppressed repetitive UVB-induced neovascularization in the SKH-1 hairless mouse skin. The induction of vascular endothelial growth factor, matrix metalloproteinase (MMP)-9 and MMP-13 expression by chronic UVB irradiation was substantially suppressed by myricetin treatment. Immunohistochemical and Western blot analyses revealed that myricetin attenuated UVB-induced hypoxia inducible factor-1alpha expression in mouse skin. In vivo kinase and pull down assay data revealed that myricetin suppressed UVB-induced phosphatidylinositol 3 (PI3)-kinase activity by direct binding with PI3-kinase. Overall, together these results suggest that the anti-photoaging, anti-skin carcinogenesis, and anti-angiogenesis effects of myricetin are due to mainly targeting Raf, Fyn, and PI3-K, respectively. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 167. doi:1538-7445.AM2012-167
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