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.

ABSTRACT4-(N-Methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone (NNK), the tobacco-specific nitrosamine, induces lung cancer in all animal species tested and is thought to contribute significantly to the high lung cancer burden associated with smoking. However, there is no report whether NNK could promote colon cancer growth. To address this hypothesis and the possible signaling pathways involved, we used SW1116 colon cancer cell line to study these biological events in vitro. Results showed that NNK, after 5-h treatment, stimulated cell proliferation, enhanced ␣7-nicotinic acetylcholine receptor (␣7-nAChR) mRNA levels and nuclear factor-B (NF-B) DNA binding activity, as well as 5-lipoxygenase and cyclooxygenase-2 protein expressions. ␣-Bungarotoxin, the specific ␣7-nAChR antagonist, inhibited these biological effects. However, 5-lipoxygenase inhibition had no effect on ␣7-nAChR mRNA expression, but significantly inhibited cell proliferation and activation of NF-B and cyclooxygenase-2, whereas NF-B-specific inhibitor caffeic acid phenethyl ester reduced both cell proliferation and cyclooxygenase expression induced by NNK without affecting ␣7-nAChR mRNA level and 5-lipoxygenase expression. Together, the present study demonstrated that NNK promoted colon cancer growth in vitro. NF-B not only conveys the biological effect of ␣7-nAChR activation but is also involved in the cross-talk between 5-lipoxygenase and cyclooxygenase-2 in response to NNK in colon cancer cell development.