Abstract 5250: Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia

Abstract

Abstract Aggressive cutaneous squamous cell carcinoma (cSCC) of the skin is the second most common type of skin cancer in the USA due to high exposure to ultraviolet-B (UVB) radiation. In our previous studies Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed UVB-induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling both of which play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against UVB-induced hyper proliferation by targeting the mTOR and FGFR signaling pathways. Pre-treatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced colony formation, mTORC1 and mTORC2 activation and FGFR2 phosphorylation in promotion sensitive JB6 epithelial cells. Further, FGFR2 was required for UVB-induced mTOR activation suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pre-treated with C3 (15mg/kg/b.w) for 2 weeks followed by a single exposure to UVB (50mj/cm2) significantly attenuated UVB-induced mTOR and FGFR activation. To further assess the role of FGFR in UVB-induced hyper proliferation, SKH-1 mice were pre-treated with AZD4547; a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (50mj/cm2). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyper proliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR pathway in mediating the effects of C3 complex in the pathogenesis of skin cancer. Citation Format: Alok R. Khandelwal, Rong Xiaohua, Tara Moore-Medlin, Oleksandr Ekshyyan, Abreo Fleurette, Xin Gu, Cherie-Ann O. Nathan. Photopreventive effect and mechanism of AZD4547 and curcumin C3 complex on UVB-induced epidermal hyperplasia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5250.