Neuronal Acetylcholine Nicotinic Receptors as New Targets for Lung Cancer Treatment

Abstract

Lung cancer is the leading cause of cancer-related deaths worldwide. Smoking accounts for approximately 70% of the cases of non- small cell lung cancer (NSCLC) and 90% of the cases of small-cell lung cancer (SCLC), although some patients develop lung cancer without a history of smoking. Nicotine is the most active addictive component of tobacco smoke. It does not initiate tumorigenesis in humans and rodents, but it alters the pathophysiology of lung cells by inducing the secretion of growth factors, neurotransmitters and cytokines, and promotes tumour growth and metastases by inducing cell cycle progression, migration, invasion, angiogenesis and the evasion of apoptosis. Most of these effects are a result of nicotine binding and activation of cell-surface neuronal nicotinic acetylcholine receptors (nAChRs) and downstream intracellular signalling cascades, and many are blocked by nAChR subtype-selective antagonists. Recent genome-wide association studies have revealed single nucleotide polymorphisms of nAChR subunits that influence nicotine dependence and lung cancer. This review describes the molecular basis of nAChR structural and functional diversity in normal and cancer lung cells, and the genetic alterations facilitating smoking-induced lung cancers. It also summarises current knowledge concerning the intracellular pathways activated by nicotine and other compounds present in tobacco smoke.

α9‐ and α7‐containing receptors mediate the pro‐proliferative effects of nicotine in the A549 adenocarcinoma cell line

“…Genome wide association studies have indicated that α5‐containing nAChRs are closely associated with the risk of lung cancer (Mucchietto et al ., ), but the underlying mechanisms are not yet well known. The published data are contradictory; Krais et al .…”

“…Tobacco smoke contains many classes of carcinogens (Hecht and Hoffmann, ) 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 metastases by inducing cell‐cycle progression, cell migration and invasion, angiogenesis and the evasion of apoptosis in a variety of tumour cells (reviewed in Egleton et al, ; Schaal and Chellappan, ; Grando, ; Mucchietto et al ., ).…”

“…It has been shown that α5 , α7 and α9 nACh receptors are expressed in various types of tumours (Grando, ; Mucchietto et al ., ).…”

Proteins and chemical chaperones involved in neuronal nicotinic receptor expression and function: an update

“…A large repertoire of nAChR subunits is present in bronchial cells and in the airway epithelium, α7 nAChRs participate in the control of the airway ion transport processes (Maouche et al, ). Various studies have also shown the involvement of nAChRs in the development and progression of lung tumours (see Schaal and Chellappan, ; Mucchietto et al, ). Linkage analyses, and candidate gene and genome‐wide association studies, have shown that variants in the human α3, α5, β4 and α9 nAChR subunit genes are associated with the risk of nicotine dependence, smoking, and lung cancer (see Improgo et al, ; Chikova et al, ).…”

“…Neuronal nicotinic ACh receptors (nAChRs) are a family of ACh‐gated cation channels that are ubiquitously expressed in virtually all neurons, where they contribute to many physiological processes in the central and peripheral nervous systems (Albuquerque et al, ; Hurst et al, ). They are also expressed in some non‐neuronal cell types where their physiological role is still being investigated (Grando, ; Mucchietto et al, ). In the brain, nAChRs are expressed at presynaptic sites (where they modulate the release of many different neurotransmitters), at postsynaptic sites (where they influence excitability), and extrasynaptically, where they participate in non‐synaptic communication (Albuquerque et al, ).…”