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 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.
Ye
Yi N
YN
Department of Pharmacology, Faculty of Medicine, The University of Hong Kong, Hong Kong, China.
Liu
Edgar S L
ES
Shin
Vivian Y
VY
Wu
William K K
WK
Luo
Jiing C
JC
Cho
Chi H
CH
D000818:Animals; D015197:Carcinogenicity Tests; D002273:Carcinogens / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D003110:Colonic Neoplasms / Q000473:pathology*; D004195:Disease Models, Animal; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000502:physiology*; D016391:Genes, src / Q000502:physiology*; D008084:Lipoxygenase / Q000502:physiology*; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009538:Nicotine / Q000494:pharmacology*; D010766:Phosphorylation; D015398:Signal Transduction / Q000502:physiology*; D014183:Transplantation, Heterologous
D002273:Carcinogens; D009538:Nicotine; D008084:Lipoxygenase; D066246:ErbB Receptors