Naproxen Inhibits UVB‐induced Basal Cell and Squamous Cell Carcinoma Development in Ptch1^+/−/SKH‐1 Hairless Mice

Abstract

Naproxen possesses anti-proliferative and pro-apoptotic effects besides its known anti-inflammatory functions. Here, we demonstrate the anti-cancer effects of naproxen against UVB-induced BCCs and 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.

New insights into the functions of Cox-2 in skin and esophageal malignancies

“…Experimentally, a rodent diet containing a selective Cox-2 inhibitor had suppressive effects on BCC formation in Ptch1 +/− mice 49 . Similarly, treatment with an NSAID, naproxen, significantly suppressed UV-induced BCC and SCC formation 50 . The role of Cox-2 in skin tumor formation was also supported by transgenic Cox-2 overexpression 51 .…”

The Role of Beta HPV Types and HPV-Associated Inflammatory Processes in Cutaneous Squamous Cell Carcinoma

“…Decreased levels of cyclooxygenase-(COX-) 2, NF-κB. and inducible nitric oxide synthase (iNOS) were identified [86].…”

Inflammation: A key process in skin tumorigenesis (Review)

“…Tumors from treated animals had lower invasiveness with increased E-cadherin expression and reduced expression of EMT markers (e.g., N-cadherin, vimentin, Snail, Twist). In BCC and SCC cells, it was shown that naproxen reduced UVB-induced skin carcinogenesis through reducing endoplasmic reticulum (ER) stress pathways (49).…”

“…The effects were associated with decreased PCNA and cyclin D1 expression, increased apoptosis and inflammation-related molecules (e.g., iNOS, COX-2 and nuclear NF-κBp65). Even remaining tumors after naproxen therapy displayed a lower aggressive potential, lower EMT marker expression (e.g., N-cadherin, vimentin, Snail and Twist) and enhanced E-cadherin expression (49).…”