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Published ahead of print on June 28, 2007, doi:10.1165/rcmb.2007-0051OC

Am. J. Respir. Cell Mol. Biol., Volume 37, Number 6, December 2007, 681-690

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Submitted on February 15, 2007
Revised on June 28, 2007

Nicotine Stimulates Human Lung Cancer Cell Growth by Inducing Fibronectin Expression

Ying Zheng1, Jeffrey D Ritzenthaler2, Jesse Roman3, and ShouWei Han2*

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

* To whom correspondence should be addressed. 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 and proliferation) and is highly expressed in tobacco-related lung disorders. Of note, reagents against the integrin {alpha}5{beta}1(antibodies, RGD peptides, {alpha}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 {alpha}7 nicotinic acetylcholine receptors ({alpha}7 nAChRs), and that {alpha}-bungarotoxin, an inhibitor of {alpha}7 nAChRs, abolished the nicotine-induced fibronectin response. The fibronectin-inducing effects of nicotine were associated with activation of ERK and PI3-K/mTOR signaling pathways, and were abrogated by inhibitors of ERK(PD98059), PI3-K(LY294002), and mTOR (rapamycin), but not by inhibitors of PKC (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 {alpha}5{beta}1 integrins as potential targets for anti-lung cancer therapies.




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