Photopreventive Effect And Mechanism Of Azd4547 And Curcumin C3 Complex On Uvb-Induced Epidermal Hyperplasia
CANCER PREVENTION RESEARCH(2016)
摘要
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.
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