Abstract 952: Nitric oxide donor sulindac inhibits photocarcinogenesis by modulating epithelial mesenchymal transition and mitogen activated protein kinase signaling in SKH-1 hairless mouse skin

Abstract

Abstract Nitric oxide (NO)-releasing non-steroid anti-inflammatory drugs (NO-NSAIDs) have been shown to have anti-proliferative, proapoptotic and cancer inhibitory properties. Here, we have investigated the effects of NO-donor sulindac on UVB-induced skin cancer development in SKH-1 hairless mice. Mice (6-8 weeks old) were divided into three groups of ten mice each, which received either vehicle (acetone), vehicle+UVB (180mJ/cm 2) or topical application of NO-sulindac (5mg/mouse)+UVB after dissolving in acetone. Mice-treated with NO-sulindac developed significantly less number of tumors (60%) compared with non-NO-sulindac treated mice and tumor volume was also less by 90% on termination of the experiment at week 30th. Immunohistochemical and western blot analyses revealed that the expression levels of proliferation markers such as proliferating cell nuclear antigen (PCNA) and cell cycle regulatory cyclin D1 were markedly diminished in tumors of NO-sulindac treated mice. However, the treatment of NO-sulindac resulted in enhanced apoptosis in skin tumors as ascertained by the increased terminal deoxynucleotidyl transferase-mediated nick end labeling (TUNEL) assay, reduced Bcl-2 and enhanced Bax expression levels in the tumors and tumor uninvolved skin. To investigate the effects of NO-sulindac on the progression of benign lesions to invasive carcinomas, we examined squamous cell carcinomas (SCC) for various epithelial-mesenchymal transition (EMT) markers. NO-sulindac decreased the expression of mesenchymal markers such as Fibronectin, N-cadherin, SNAI, Slug and Twist whereas the epithelial polarity marker E-cadherin was found to be increased compared to the SCCs of non-NO-sulindac treated group. Down regulation of EMT by NO-sulindac was associated with a remarkable diminution of UVB-induced phosphorylation MAPK proteins such as, extracellular signal-regulated kinase 1/2 (Erk 1/2), c-Jun-NH2 terminal kinase 1/2 (JNK1/2) and p38 in both UVB-exposed skin and skin tumors. Together our results suggest that NO-sulindac is a potential chemopreventive agent for photocarcinogenesis and that inhibition of photocarcinogenesis by NO-sulindac is associated with the inhibition of EMT and MAPK protein expression in skin tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 952.