Naproxen Inhibits UVB‐induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1+/−/SKH‐1 Hairless Mice1. (9th May 2017)

• Record Type: Journal Article
• Authors: Chaudhary, Sandeep C.; Waseem, Mohammad; Rana, Mehtab; Xu, Hui; Kopelovich, Levy; Elmets, Craig A.; Athar, Mohammad
• Is Part Of: Photochemistry and photobiology. Volume 93:Number 4(2017)
• Page Start: 1016
• Page End: 1024
• Publication Date: 2017-05-09
• Subjects: Photochemistry -- Periodicals; Light -- Physiological effect -- Periodicals; 541.35
• DOI: 10.1111/php.12758
• Languages: English
• ISSNs: 0031-8655

Abstract

Abstract: 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 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 ATF4, p‐eIF2 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. Abstract : Cancer chemoprevention efficacy of naproxen against UVB‐induced cutaneous neoplasm. Naproxen treatment reduces UVB‐induced basal cell carcinoma (BCC) and squamous cell carcinoma (SCC) development in Ptch1 +/− /SKH‐1 hairless mice. It inhibits tumor cell proliferation, NFκB‐mediated inflammatory responses, epithelial mesenchymal transition (EMT) and induces apoptosis. The mechanism involves enhancing unfolded protein response signaling (UPR)‐related proteins eIF2α, ATF4, and CHOP. Abrogating expression of CHOP diminishes these effects of naproxen on tumor cells.