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Nicotine Promoted Colon Cancer Growth via Epidermal Growth Factor Receptor, c-Src, and 5-Lipoxygenase-Mediated Signal Pathway
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 impo...
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Published in: | The Journal of pharmacology and experimental therapeutics 2004-01, Vol.308 (1), p.66-72 |
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Main Authors: | , , , , , |
Format: | Article |
Language: | English |
Subjects: | |
Citations: | Items that this one cites Items that cite this one |
Online Access: | Get full text |
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Summary: | 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. |
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ISSN: | 0022-3565 1521-0103 |
DOI: | 10.1124/jpet.103.058321 |