Abstract
Gastric cancer incidence demonstrates a strong etiologic association with smoking. Nicotine, the major component in tobacco, is a survival agonist that inhibits apoptosis induced by certain chemotherapeutic agents, but the precise mechanisms involved remain largely unknown. Recently studies have indicated that α5-nicotinic acetylcholine receptor (α5-nAChR) is highly associated with lung cancer risk and nicotine dependence. Nevertheless, no information has been available about whether nicotine also affects proliferation of human gastric cancer cells through regulation of α5-nAChR. To evaluate the hypothesis that α5-nAChR may play a role in gastric cancer, we investigated its expression in gastric cancer tissues and cell lines. The expression of α5-nAChR increased in gastric cancer tissue compared with para-carcinoma tissues. In view of the results, we proceeded to investigate whether nicotine inhibits cisplatin-induced apoptosis via regulating α5-nAChR in gastric cancer cell. The results showed that nicotine significantly promoted cell proliferation in a dose and time-dependent manner through α5-nAChR activation in human gastric cells. Furthermore, nicotine inhibited apoptosis induced by cisplatin. Silence of α5-nAChR ablated the protective effects of nicotine. However, when co-administrating LY294002, an inhibitor of PI3K/AKT pathway, an increased apoptosis was observed. This effect correlated with the induction of Bcl-2, Bax, Survivin and Caspase-3 by nicotine in gastric cell lines. These results suggest that exposure to nicotine might negatively impact the apoptotic potential of chemotherapeutic drugs and that α5-nAChR/AKT signaling plays a key role in the anti-apoptotic activity of nicotine induced by cisplatin.
Highlights
Gastric cancer is one of the major causes of cancer deaths in the world
The analysis of clinical specimens indicated that α5-nicotinic acetylcholine receptors (nAChRs) expression is generally higher in tumor cells compared with para-carcinoma cells
The results showed a trend that the positive rate of α5-nAchR expression was higher in patients with nicotine intake history than patients without nicotine intake history
Summary
Gastric cancer is one of the major causes of cancer deaths in the world. Both genetic and environmental factors are involved in gastric carcinogenesis. Previous findings have unraveled the strong association between cigarette smoke and gastric cancer incidence [1,2,3], the detailed mechanism has not been fully studied. A major component of cigarette smoke, has been shown to be involved in the initiation, promotion, and even progression of several tumors including gastric cancer. Studies have demonstrated that nicotine stimulated the proliferation of human gastric cancer cells through its interaction with α7-nAChR [4, 5]. No information has been available about whether nicotine affects proliferation of human gastric cancer cells through regulation of α5-nAChR
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