PHARMACOLOGICAL AND FUNCTIONAL CHARACTERISATION OF NEURONAL NICOTINIC ACETYLCHOLINE RECEPTORS IN LUNG CANCER CELL LINES: A CHALLENGE FOR NEW THERAPEUTICAL STRATEGIES?

Lung cancer is the leading cause of cancer-related deaths worldwide and cigarette smoking is related to 90% of all deaths due to lung cancer. Tobacco smoke contains many classes of carcinogens and, although nicotine, the addictive and most active component of tobacco smoke, is unable to initiate tumourigenesis in humans and rodents, it promotes tumour growth and metastasis by inducing cell-cycle progression, cell migration, angiogenesis and the evasion of apoptosis in a variety of systems. Nicotine and its metabolites are highly lipophilic compounds that bind and activate a family of ligand-gated cation channels (the neuronal nicotinic acetylcholine receptors, nAChRs) that are widely expressed in the central and peripheral nervous systems. Over the last few decades, the extra-neuronal localisation of nAChRs has been demonstrated in a large number of cell types including endothelial cells, glia, immune cells, lung tissue and cancer cells, indicating that they might have functions well beyond simple neurotransmission. Recent studies have shown that most of the tumour-promoting effects of nicotine are primarily due to the binding and the activation of nAChRs, which lead to downstream intracellular signalling cascades. However, identifying the receptor subtypes expressed in lung tumour cells and their signalling pathways is still in its early stage. For these reasons, we investigated the pathophysiological role of nAChRs in lung cancer cells. We found that different non-small cell lung cancer (NSCLC) cells express distinctive nicotinic receptor subtypes and that this variety affects nicotine-induced proliferation and migration. In the A549 adenocarcinoma cell line, nAChRs containing the α7, α9 and α5 subunits regulate not only the nicotine-induced cell proliferation and migration but also the activation of anti-apoptotic and proliferative pathways. Blocking nAChRs containing the α7 or α9 or α5 subunits with specific toxins or silencing their expression by means of subunit-specific siRNAs abolishes the nicotine-induced proliferation, migration and signalling. Prompted by these results, we also studied oxystylbene compounds previously characterised by our group and started to syntehesise some new oxystylbene/resveratrol derivatives with specific modifications. We found that these 4-oxystilbene derivates act on both α7 and α9-containing receptors and block NSCLC cell proliferation and viability in a dose-dependent manner. These results highlight the pathophysiological role of specific nAChR subtypes in promoting NSCLC cell growth and migration and raise the possibility of targeting them in order to treat tobacco related cancer.