Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia

Aggressive cutaneous squamous cell carcinoma (cSCC) skin is the second most common type of skin cancer in the United States due to high exposure to ultraviolet B (UVB) radiation. In our previous studies, Curcumin C3 complex (C3), a standardized preparation of three curcumonoids, delayed [NB -induced tumor incidence and inhibited multiplicity. Exposure to UVB activates mTOR and FGFR signaling that play a key role in skin tumorigenesis. The purpose of this study was to investigate the efficacy of C3 complex to afford protection against acute UVB-induced hyperproliferation by targeting the mTOR and FGFR signaling pathways. Pretreatment with C3 complex significantly inhibited UVB-induced FGF-2 induction, FGF-2-induced cell proliferation, progression and colony formation, mTORC1 and mTORC2 activation, and FGFR2 phosp horylation in the promotion -sensitive J116 cells epithelia] cells. Further, [CFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in LAT-induced inTOR signaling. SK1-1-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to MB (180 mj/cm2) significantly attenuated UVB-induced mTORCI, mTORC2, and FGFR2 activation. To further assess the role of FGFR in 1113 induced hyperproliferation, SKH-1 mice were pretreated with AZD4547 (5 mg/kg/b.w.); a selective pan-FGFR kinase inhibitor followed by single exposure to UVB (180 ini/cm2). AZD4547 significantly inhibited UVB-induced MTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVBuced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer. Cancer Prey Hes;.9(4); 296-304. 2016 AACR.