Role and therapeutic potential of targeting nicotinic receptor in non small cell lung cancers

Lung cancer is the leading cause of cancer death worldwide and smoking accounts for approximately 70% of non-small cell lung cancer (NSCLC) and 90% of small cell lung cancer (SCLC) cases, although there is a subset of patients who develop lung cancer without a history of smoking. Nicotine, the addictive constituent of tobacco, and its derived carcinogenic nitrosamines, contribute to promote tumour growth and metastasis by inducing cell-cycle progression, migration and invasion by regulating different signaling pathways mainly through the activation of nicotinic acetylcholine receptors (nAChRs). nAChRs are an heterogeneous family of ligand gated cation channels widely distributed not only in the central and peripheral nervous system but also in extraneuronal tissues. nAChRs are present both in normal and malignant cells and by altering cell proliferation may contribute to the transformed phenotype typical of cancer cells. Several studies have shown that the α7 homomeric nAChR is implicated in lung tumors and recent genetic studies, have indicated that other nAChR subtypes are involved in lung cancer susceptibility and predisposition. In this work we have analysed the nAChR expression in lung cancer cell lines (A549 and H1975) and lung cancer tissues obtained by patients. We have investigated the effects of nicotine in regulating cell proliferation and cell migration. We have therefore studied the intracellular signalling of nicotine and we are now investigating the role of drugs targeting nAChRs. Our results show the presence of α7–containing receptors in A549 cell line but not in H1975, while tumour samples show an increase in the level of CHRNA5 subunit mRNA with no significative change of CHRNA7 mRNAs. Nicotine, in a dose-dependent manner, significantly increases the A549 cell viability and proliferation but has no effect on H1975 cells. To determine whether the α7 nAChR might mediate the nicotine-induced proliferation we have used both α7-agonists (i.e. ICH3) and antagonists (i.e. α-bungarotoxin (α-bgtx) and methyllycaconitine (MLA)). We have found that ICH3 promotes A549 proliferation while both α-bgtx and MLA block the nicotine-induced proliferation in this cell line. Nicotine is also able to enhance the migration of A549 cells and induces a selective time‐dependent activation of phospho-ERK and phospho­AKT pathways in A549 cells. Collectively our data suggest that nicotine promotes proliferation, invasion and migration of NSCLC A549 cell line by activating the AKT/ERK pathway while H1975 do not show any effects after nicotine-treatments. α7-antagonists block nicotine-mediated effects and this result will may help us to find new specific therapeutic strategies.