This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Du, B. Articles by Dannenberg, A. J. Search for Related Content PubMed PubMed Citation Articles by Du, B. Articles by Dannenberg, A. J. Related Collections Oncogenesis Oncogenesis: In Vitro

Tobacco Smoke Stimulates the Transcription of Amphiregulin in Human Oral Epithelial Cells: Evidence of a Cyclic AMP-Responsive Element Binding Protein–Dependent Mechanism

Departments of ¹ Medicine and ² Cardiothoracic Surgery, Weill Medical College of Cornell University, New York, New York and ³ Division of Cancer Prevention, National Cancer Institute, Bethesda, Maryland

Requests for reprints: Andrew J. Dannenberg, New York Presbyterian-Cornell, Room F-206, 525 East 68th Street, New York, NY 10021. Phone: 212-746-4403; Fax: 212-746-4885; E-mail: ajdannen{at}med.cornell.edu.

Activation of epidermal growth factor receptor (EGFR)–mediated signaling has been implicated in the pathogenesis of tobacco smoke–induced cancers. Recently, elevated levels of amphiregulin, a ligand of the EGFR, were found in the oral mucosa of smokers. The main objective of this study was to elucidate the mechanism by which tobacco smoke induces amphiregulin. Treatment of a nontumorigenic human oral epithelial cell line (MSK-Leuk1) with a saline extract of tobacco smoke stimulated amphiregulin (AR) transcription resulting in increased amounts of amphiregulin mRNA and protein. Tobacco smoke stimulated the cyclic AMP (cAMP)protein kinase A (PKA) pathway leading to increased cAMP-responsive element binding protein–dependent activation of AR transcription. These inductive effects of tobacco smoke were dependent on the aryl hydrocarbon receptor (AhR). In fact, -naphthoflavone, an AhR antagonist, blocked tobacco smoke–mediated induction of binding of cAMP-responsive element binding protein to the AR promoter and thereby suppressed the induction of amphiregulin. Notably, treatment of MSK-Leuk1 cells with tobacco smoke or exogenous amphiregulin stimulated DNA synthesis. An inhibitor of EGFR tyrosine kinase or a neutralizing antibody to amphiregulin abrogated the increase in DNA synthesis mediated by tobacco smoke. Taken together, these findings suggest that tobacco smoke stimulated a signaling pathway comprised of AhRcAMPPKA resulting in enhanced AR transcription and increased DNA synthesis. The ability of tobacco smoke to induce amphiregulin and thereby enhance DNA synthesis is likely to contribute to the procarcinogenic effects of tobacco smoke.

This article has been cited by other articles:

				H.-S. Seo, D. D. Liu, B. N. Bekele, M.-K. Kim, K. Pisters, S. M. Lippman, I. I. Wistuba, and J. S. Koo Cyclic AMP Response Element-Binding Protein Overexpression: A Feature Associated with Negative Prognosis in Never Smokers with Non-Small Cell Lung Cancer Cancer Res., August 1, 2008; 68(15): 6065 - 6073. [Abstract] [Full Text] [PDF]

				Z. H. Gumus, B. Du, A. Kacker, J. O. Boyle, J. M. Bocker, P. Mukherjee, K. Subbaramaiah, A. J. Dannenberg, and H. Weinstein Effects of Tobacco Smoke on Gene Expression and Cellular Pathways in a Cellular Model of Oral Leukoplakia Cancer Prevention Research, July 1, 2008; 1(2): 100 - 111. [Abstract] [Full Text] [PDF]

				M. Yamada, Y. Ichikawa, S. Yamagishi, N. Momiyama, M. Ota, S. Fujii, K. Tanaka, S. Togo, S. Ohki, and H. Shimada Amphiregulin Is a Promising Prognostic Marker for Liver Metastases of Colorectal Cancer Clin. Cancer Res., April 15, 2008; 14(8): 2351 - 2356. [Abstract] [Full Text] [PDF]

				M. Rumelhard, K. Ramgolam, R. Hamel, F. Marano, and A. Baeza-Squiban Expression and role of EGFR ligands induced in airway cells by PM2.5 and its components Eur. Respir. J., December 1, 2007; 30(6): 1064 - 1073. [Abstract] [Full Text] [PDF]

				B. Du, H. Leung, K.M. F. Khan, C. G. Miller, K. Subbaramaiah, D. J. Falcone, and A. J. Dannenberg Tobacco Smoke Induces Urokinase-Type Plasminogen Activator and Cell Invasiveness: Evidence for an Epidermal Growth Factor Receptor Dependent Mechanism Cancer Res., September 15, 2007; 67(18): 8966 - 8972. [Abstract] [Full Text] [PDF]

				J. Zhao, R. Harper, A. Barchowsky, and Y. P. P. Di Identification of multiple MAPK-mediated transcription factors regulated by tobacco smoke in airway epithelial cells Am J Physiol Lung Cell Mol Physiol, August 1, 2007; 293(2): L480 - L490. [Abstract] [Full Text] [PDF]

				R. Wu, L. Zhang, M. S. Hoagland, and H. I. Swanson Lack of the Aryl Hydrocarbon Receptor Leads to Impaired Activation of AKT/Protein Kinase B and Enhanced Sensitivity to Apoptosis Induced via the Intrinsic Pathway J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 448 - 457. [Abstract] [Full Text] [PDF]

				S. SH. Choi, M. A. Miller, and P. A. Harper In Utero Exposure to 2,3,7,8-Tetrachlorodibenzo-p-dioxin Induces Amphiregulin Gene Expression in the Developing Mouse Ureter Toxicol. Sci., November 1, 2006; 94(1): 163 - 174. [Abstract] [Full Text] [PDF]

				S. Kalyankrishna and J. R. Grandis Epidermal Growth Factor Receptor Biology in Head and Neck Cancer J. Clin. Oncol., June 10, 2006; 24(17): 2666 - 2672. [Abstract] [Full Text] [PDF]