title: Photopreventive Effect and Mechanism of AZD4547 and Curcumin C3 Complex on UVB-Induced Epidermal Hyperplasia.
abstract: Aggressive cutaneous squamous cell carcinoma (cSCC) of the 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 UVB-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 phosphorylation in the promotion-sensitive JB6 cells epithelial cells. Further, FGFR was critical for UVB-induced mTOR activation, suggesting an important role of FGFR2 in UVB-induced mTOR signaling. SKH-1 mice pretreated with C3 (15 mg/kg/b.w.) for 2 weeks followed by a single exposure to UVB (180 mj/cm(2)) significantly attenuated UVB-induced mTORC1, mTORC2, and FGFR2 activation. To further assess the role of FGFR in UVB-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 mj/cm(2)). AZD4547 significantly inhibited UVB-induced mTORC1 and mTORC2 activation, epidermal hyperplasia and hyperproliferation. Our studies underscore the importance of FGFR signaling in UVB-induced acute skin changes and the role of FGFR/mTOR signaling in mediating the effects of C3 complex in the pathogenesis of skin cancer.
authors: Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Alok R
authors: AR
authors: Khandelwal
authors: Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Xiaohua
authors: X
authors: Rong
authors: Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Tara
authors: T
authors: Moore-Medlin
authors: Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Oleksandr
authors: O
authors: Ekshyyan
authors: Department of Pathology, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Fleurette
authors: F
authors: Abreo
authors: Department of Pathology, LSU-Health Shreveport, Shreveport, Louisiana.
authors: Xin
authors: X
authors: Gu
authors: Department of Otolaryngology-Head and Neck Surgery, LSU-Health Shreveport, Shreveport, Louisiana. Department of Surgery, Overton Brooks Veterans Medical Center, Shreveport, Louisiana. cnatha@lsuhsc.edu.
authors: Cherie-Ann O
authors: CA
authors: Nathan
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001549:Benzamides / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000517:prevention & control; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects / Q000528:radiation effects; D003474:Curcumin / Q000494:pharmacology*; D004817:Epidermis / Q000187:drug effects / Q000528:radiation effects*; D005260:Female; D016222:Fibroblast Growth Factor 2 / Q000097:blood / Q000378:metabolism; D006801:Humans; D006965:Hyperplasia; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D051379:Mice; D008812:Mice, Hairless; D046912:Multiprotein Complexes / Q000378:metabolism; D010766:Phosphorylation; D010879:Piperazines / Q000494:pharmacology*; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D011720:Pyrazoles / Q000494:pharmacology*; D051497:Receptor, Fibroblast Growth Factor, Type 2 / Q000378:metabolism*; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000517:prevention & control; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism; D014466:Ultraviolet Rays / Q000009:adverse effects*
chemical_list: C572463:AZD4547; D000970:Antineoplastic Agents; D001549:Benzamides; D046912:Multiprotein Complexes; D010879:Piperazines; D047428:Protein Kinase Inhibitors; D011720:Pyrazoles; D016222:Fibroblast Growth Factor 2; C496354:Fgfr2 protein, mouse; D051497:Receptor, Fibroblast Growth Factor, Type 2; D000076222:Mechanistic Target of Rapamycin Complex 1; D000076225:Mechanistic Target of Rapamycin Complex 2; D058570:TOR Serine-Threonine Kinases; D003474:Curcumin