QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.103.058321v1 308/1/66    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map 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 Ye, Y. N. Articles by Cho, C. H. Search for Related Content PubMed PubMed Citation Articles by Ye, Y. N. Articles by Cho, C. H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Hazardous Substances DB NICOTINE NICOTINE TARTRATE

GASTROINTESTINAL, HEPATIC, PULMONARY, AND RENAL

Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway

Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China (Y.N.Y., E.S.L.L., V.Y.S., W.K.K.W., J.C.L., C.H.C.); and Department of Pharmacology, Faculty of Medicine, Zhejiang University, Hangzhou, China (Y.N.Y.)

Nicotine [3-(1-methyl-2-pyrrolidinyl)-pyridine], a major alkaloid in tobacco, has been implicated as playing a role in carcinogenesis. Our previous study showed that passive cigarette smoking promoted inflammation-associated colonic adenoma formation in mice, and 5-lipoxygenase (5-LOX) plays an important role in this process. In the present study, we aimed to investigate whether nicotine could stimulate colon cancer cell proliferation and tumor growth in nude mice xenograft model and the possible mechanisms involved. Results showed that nicotine stimulated SW1116 colon cancer cell proliferation in a dose-dependent manner. Epidermal growth factor receptor (EGFR) and c-Src phosphorylation levels together with protein expression of 5-LOX were also significantly enhanced in this proliferation process. Inhibitors of EGFR and c-Src alleviated the actions of nicotine on cell proliferation and 5-LOX protein expression. Combination of both agents produced additive effect. In contrast, 5-LOX inhibitor had no direct effect on the phosphorylation levels of EGFR and c-Src and yet inhibited cell proliferation. In the colon cancer xenograft model, nicotine also significantly enhanced tumor growth. This acceleration of tumor growth corresponded well with increased vascularization and its proangiogenic factors. Inhibitors of EGFR, c-Src, and 5-LOX all significantly impeded the tumor growth induced by nicotine. Together, nicotine can promote colonic tumorigenesis both in vitro and in vivo. Activation of the phosphorylated form of EGFR and c-Src followed by an increased 5-LOX expression are the prime pathogenic mechanisms in the tumorigenic process in the colon.

Address correspondence to: Prof. C. H. Cho, Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China. E-mail: chcho{at}hkusua.hku.hk

This article has been cited by other articles:

				J. Guo, S. Ibaragi, T. Zhu, L.-Y. Luo, G.-F. Hu, P. S. Huppi, and C. Y. Chen Nicotine Promotes Mammary Tumor Migration via a Signaling Cascade Involving Protein Kinase C and cdc42 Cancer Res., October 15, 2008; 68(20): 8473 - 8481. [Abstract] [Full Text] [PDF]

				R.-J. Chen, Y.-S. Ho, H.-R. Guo, and Y.-J. Wang Rapid Activation of Stat3 and ERK1/2 by Nicotine Modulates Cell Proliferation in Human Bladder Cancer Cells Toxicol. Sci., August 1, 2008; 104(2): 283 - 293. [Abstract] [Full Text] [PDF]

				P. Dasgupta, R. Kinkade, B. Joshi, C. DeCook, E. Haura, and S. Chellappan Nicotine inhibits apoptosis induced by chemotherapeutic drugs by up-regulating XIAP and survivin PNAS, April 18, 2006; 103(16): 6332 - 6337. [Abstract] [Full Text] [PDF]

				V. Y. Shin, W. K.K. Wu, K.-M. Chu, H. P.S. Wong, E. K.Y. Lam, E. K.K. Tai, M. W.L. Koo, and C.-H. Cho Nicotine Induces Cyclooxygenase-2 and Vascular Endothelial Growth Factor Receptor-2 in Association with Tumor-Associated Invasion and Angiogenesis in Gastric Cancer Mol. Cancer Res., November 1, 2005; 3(11): 607 - 615. [Abstract] [Full Text] [PDF]

				E. R. Gritz, C. Dresler, and L. Sarna Smoking, The Missing Drug Interaction in Clinical Trials: Ignoring the Obvious Cancer Epidemiol. Biomarkers Prev., October 1, 2005; 14(10): 2287 - 2293. [Abstract] [Full Text] [PDF]

				J. K. S. Ko and C.-H. Cho The Diverse Actions of Nicotine and Different Extracted Fractions from Tobacco Smoke against Hapten-Induced Colitis in Rats Toxicol. Sci., September 1, 2005; 87(1): 285 - 295. [Abstract] [Full Text] [PDF]

				N. H. Kleinsasser, A. W. Sassen, M. P. Semmler, U. A. Harreus, A.-K. Licht, and E. Richter The Tobacco Alkaloid Nicotine Demonstrates Genotoxicity in Human Tonsillar Tissue and Lymphocytes Toxicol. Sci., August 1, 2005; 86(2): 309 - 317. [Abstract] [Full Text] [PDF]

				M.-C. Etienne-Grimaldi, S. Pereira, N. Magne, J.-L. Formento, M. Francoual, X. Fontana, F. Demard, O. Dassonville, G. Poissonnet, J. Santini, et al. Analysis of the dinucleotide repeat polymorphism in the epidermal growth factor receptor (EGFR) gene in head and neck cancer patients Ann. Onc., June 1, 2005; 16(6): 934 - 941. [Abstract] [Full Text] [PDF]

				Y.N. Ye, W.K.K. Wu, V.Y. Shin, I.C. Bruce, B.C.Y. Wong, and C.H. Cho Dual inhibition of 5-LOX and COX-2 suppresses colon cancer formation promoted by cigarette smoke Carcinogenesis, April 1, 2005; 26(4): 827 - 834. [Abstract] [Full Text] [PDF]