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Naproxen Inhibits UVB ‐induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1 +/− / SKH ‐1 Hairless Mice
Author(s) -
Chaudhary Sandeep C.,
Waseem Mohammad,
Rana Mehtab,
Xu Hui,
Kopelovich Levy,
Elmets Craig A.,
Athar Mohammad
Publication year - 2017
Publication title -
photochemistry and photobiology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.818
H-Index - 131
eISSN - 1751-1097
pISSN - 0031-8655
DOI - 10.1111/php.12758
Subject(s) - apoptosis , chop , unfolded protein response , cancer research , chemistry , carcinogenesis , hairless , naproxen , vimentin , cyclin d1 , cell growth , microbiology and biotechnology , biology , immunology , medicine , cell cycle , pathology , biochemistry , immunohistochemistry , alternative medicine , gene
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 ( BCC s) and squamous cell carcinoma ( SCC s) in a highly susceptible murine model of UVB carcinogenesis. Naproxen significantly inhibited UVB ‐induced BCC s and SCC s in this model. Tumor number and volume were significantly decreased ( P < 0.005 and P < 0.05, respectively). Inhibition in UVB ‐induced SCC s and BCC s 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 NF κ Bp65 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 ATF 4, p‐ eIF 2 α 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.