Naproxen Inhibits UVB-induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1+/-/SKH-1 Hairless Mice.
Naproxen possesses anti-proliferative and pro-apoptotic effects besides its known anti-inflammatory functions. Here, we demonstrate the anticancer effects of naproxen against UVB-induced basal cell carcinoma (BCCs) and squamous cell carcinoma (SCCs) in a highly susceptible murine model of UVB carcinogenesis. Naproxen significantly inhibited UVB-induced BCCs and SCCs in this model. Tumor number and volume were significantly decreased (P < 0.005 and P < 0.05, respectively). Inhibition in UVB-induced SCCs and BCCs was 77% and 86%, respectively, which was associated with reduced PCNA and cyclin D1 and increased apoptosis. As expected, inflammation-related iNOS, COX-2 and nuclear NFκBp65 were also diminished by naproxen treatment. Residual tumors excised from naproxen-treated animal were less invasive and showed reduced expression of epithelial-mesenchymal transition (EMT) markers N-cadherin, Vimentin, Snail and Twist with increased expression of E-cadherin. In BCC and SCC cells, naproxen-induced apoptosis and activated unfolded protein response (UPR) signaling with increased expression of ATF4, p-eIF2α and CHOP. Employing iRNA-based approaches, we found that naproxen-induced apoptosis was regulated by CHOP as sensitivity of these cutaneous neoplastic cells for apoptosis was significantly diminished by ablating CHOP. In summary, these data show that naproxen is a potent inhibitor of UVB-induced skin carcinogenesis. ER stress pathway protein CHOP may play an important role in inducing apoptosis in cancer cells.
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Sandeep C
SC
Chaudhary
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Mohammad
M
Waseem
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Mehtab
M
Rana
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Hui
H
Xu
Department of Medicine, Weill Cornell Medical College, New York, NY.
Levy
L
Kopelovich
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Craig A
CA
Elmets
Department of Dermatology, VH509 University of Alabama at Birmingham, Birmingham, AL.
Mohammad
M
Athar
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology*; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D002280:Basal Cell Carcinoma / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D002294:Carcinoma, Squamous Cell / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D045744:Cell Line, Tumor; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D006801:Humans; D008812:Mice, Hairless; D008822:Mice, Transgenic; D009288:Naproxen / Q000494:pharmacology*; D009381:Neoplasms, Radiation-Induced / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D000072081:Patched-1 Receptor / Q000235:genetics*; D012878:Skin Neoplasms / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D014466:Ultraviolet Rays; D056811:Unfolded Protein Response
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000072081:Patched-1 Receptor; C000606240:Ptch1 protein, mouse; D009288:Naproxen