Lung cancer is the second most common cancer and the leading cause of cancer death among both men and women. Although, tobacco smoking is the dominant etiologic factor responsible for the vast majority of lung cancers, other factors such as asbestos, pollutants, polycyclic aromatic hydrocarbons, nutritional and dietary factors which can cause pulmonary inflammation can also drive carcinogenesis by altering cellular and molecular targets and pathways that are crucial to normal tissue homeostasis. However, the molecular signaling events specific to the pulmonary inflammation and their effects on pulmonary cells leading to carcinogenesis are poorly understood. Hence, we investigated the role of polyol pathway enzyme aldose reductase (AR), an oxidative stress response protein that catalyzes the reduction of lipid peroxidation -derived lipid aldehydes and their glutathione conjugates, in the mediation of carcinogenic signals leading to lung cancer. We examined the effect of pharmacological and siRNA -mediated inhibition of AR on in vitro human lung carcinoma cell line A549 growth as well as tumor growth in nude mice xenografts. We have also examined the molecular mechanisms by which AR inhibition prevents carcinogenic signaling events that cause lung cancer cell growth. Treatment of A549 cells with AR inhibitors prevented the activation of NF-kB and expression of NF-kB- dependent inflammatory markers such as iNOS and Cox-2. AR inhibition also prevented the proliferation of cultured human lung cancer cells. Further, AR inhibition significantly arrested the tumor growth in nude mice bearing lung adenocarcinoma xenografts. Similar results were observed in AR-siRNA treated nude mice xenografts. Immunohistochemical analysis of nude mice tumor cross sections indicated that AR inhibition prevents activation of iNOS, Cox-2, AR and NF-kB. Our studies thus strongly suggest that AR may be a critical regulator of signaling pathway(s) that cause lung cancer. Hence, disrupting these signals by AR inhibition could be a novel preventive approach in lung cancer progression.

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 3233.