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Nicotine Stimulates Human Lung Cancer Cell Growth by Inducing Fibronectin Expression

¹ Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Atlanta, Georgia; ² Atlanta Veterans Affairs Medical Center, Atlanta, Georgia; and ³ Department of Obstetrics and Gynecology, West China Second University Hospital, Sichuan University, Chengdu, China

Correspondence and requests for reprints should be addressed to ShouWei Han, M.D., Ph.D., Division of Pulmonary, Allergy and Critical Care Medicine, Emory University School of Medicine, Whitehead Bioresearch Building, 615 Michael Street, Suite 205-M, Atlanta, GA 30322. E-mail: shan2{at}emory.edu

The mechanisms by which tobacco promotes lung cancer remain incompletely understood. Herein, we report that nicotine, a major component of tobacco, promotes the proliferation of cultured non–small cell lung carcinoma (NSCLC) cells; this effect was most noticeable at 5 days. However, nicotine had no effect on apoptosis of NSCLC cells. In experiments designed to unveil the mechanisms for this effect, we found that nicotine also stimulated mRNA and protein expression of fibronectin. Fibronectin is a matrix glycoprotein that regulates important cellular processes (e.g., adhesion, proliferation, and differentiation) and is highly expressed in tobacco-related lung disorders. Of note, reagents against the integrin 51 (antibodies, RGD peptides, 5 shRNA) blocked the mitogenic effects of nicotine. Thus, nicotine stimulated NSCLC cell proliferation indirectly via fibronectin induction. We then focused on the mechanisms responsible for nicotine-induced fibronectin expression in NSCLC cells and found that nicotine stimulated the surface expression of 7 nicotinic acetylcholine receptor (7 nAChR), and that -bungarotoxin, an inhibitor of 7 nAChR, abolished the nicotine-induced fibronectin response. The fibronectin-inducing effects of nicotine were associated with activation of extracellular signal–regulated kinase (ERK) and phosphoinositide 3-kinase (PI3-K)/mammalian target of rapamycin (mTOR) signaling pathways, and were abrogated by inhibitors of ERK (PD98059), PI3-K (LY294002), and mTOR (rapamycin), but not by inhibitors of protein kinase (PK)C (calphostin C) and PKA (H89). These observations suggest that nicotine stimulates NSCLC proliferation through induction of fibronectin, and that these events are mediated through nAChR-mediated signals that include ERK and PI3-K/mTOR pathways. This work highlights the role of fibronectin and 51 integrins as potential targets for anti–lung cancer therapies.

Key Words: nicotine • fibronectin • ERK • PI3-K/mTOR • human lung carcinoma cells

CLINICAL RELEVANCE This work unveils a novel role for fibronectin and matrix-binding integrins in tobacco-related lung carcinoma cell progression, and points to potential new targets for the development of adjuvant therapies in tobacco-related tumors.

 

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