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Journal of Oncology
Volume 2011, Article ID 561862, 16 pages
http://dx.doi.org/10.1155/2011/561862
Research Article

Molecular Mechanisms of Cigarette Smoke-Induced Proliferation of Lung Cells and Prevention by Vitamin C

Department of Biotechnology and Dr. B. C. Guha Centre for Genetic Engineering and Biotechnology, Calcutta University College of Science, 35 Ballygunge Circular Road, Kolkata 700019, India

Received 14 December 2010; Revised 12 February 2011; Accepted 24 February 2011

Academic Editor: Aditi Chatterjee

Copyright © 2011 Neekkan Dey et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Lung cancer is the leading cause of cancer dearth. Cigarette smoking is the strongest risk factor for developing lung cancer, which is conceivably initiated by proliferation. Here, we show that low concentration of aqueous extract of cigarette smoke (AECS) causes excessive proliferation of human lung epithelial cells (A549) without any apoptotic cell death. The causative factor responsible for AECS-induced proliferation has been identified as p-benzoquinone (p-BQ). Coimmunoprecipitation and immunoblot experiments indicate that p-BQ binds with epidermal growth factor receptor (EGFR). However, in contrast to EGF, it causes aberrant phosphorylation of EGFR that lacks c-Cbl-mediated ubiquitination and degradation resulting in persistent activation of EGFR. This is followed by activation of Hras + Kras and the downstream survival and proliferative signaling molecules Akt and ERK1/2, as well as the nuclear transcription factors c-Myc and c-Fos. Vitamin C and/or antibody to p-BQ prevents AECS/p-BQ-induced proliferation of lung cells apparently by inactivating p-BQ and thereby preventing activation of EGFR and the downstream signaling molecules. The results suggest that vitamin C and/or antibody to p-BQ may provide a novel intervention for preventing initiation of lung cancer in smokers.