From smoking to lung cancer: the CHRNA5/A3/B4 connection

Abstract

Nicotinic acetylcholine receptors (nAChRs) are ligand-gated ion channels that modulate key physiological processes ranging from neurotransmission to cancer signaling. These receptors are activated by the neurotransmitter, acetylcholine, and the tobacco alkaloid, nicotine. Recently, the gene cluster encoding the α3, α5 and β4 nAChR subunits received heightened interest after a succession of linkage analyses and association studies identified multiple single nucleotide polymorphisms (SNPs) in these genes that are associated with an increased risk for nicotine dependence and lung cancer. It is not clear whether the risk for lung cancer is direct or an effect of nicotine dependence, as evidence for both scenarios exist. Here, we summarize the body of work implicating nAChRs in the pathogenesis of lung cancer, with special focus on the clustered nAChR subunits and their emerging role in this disease state.

The SNP rs931794 in 15q25.1 Is Associated with Lung Cancer Risk: A Hospital-Based Case-Control Study and Meta-Analysis

“…The receptors bind to nicotine, N’-nitrosonornicotine and other potential carcinogens, leading to genetic mutations and neoplastic transformation[34]. SNPs in CHRNA5-CHRNA3-CHRNB4 could be able to influence the binding function, thus influence individual lung cancer risk.…”

The alpha9 Nicotinic Acetylcholine Receptor is the Key Mediator in Nicotine-enhanced Cancer Metastasis in Breast Cancer Cells

“…8,28 nAchRs have been noted to promote a nicotine-stimulated epithelial-to-mesenchymal transition (EMT) in a variety of human cancer cell lines, especially in small cell lung cancer and non-small cell lung cancer. 12,13 Several studies have reported roles of nAchRs in carcinogenesis, proliferation, angiogenesis, inhibition of apoptosis and metastasis in breast, lung and colon cancers. 14e17, 29,30 In studies of colon cancer and gastric cancer, a7-nAChR was found to play a dominant role in mediating cancer progression and metastasis.…”

Nicotinic acetylcholine receptor ligands, a patent review (2006 – 2011)

“…These pathways need also to be considered when developing nAChR drugs for chronic treatment. The heteromeric α3α5β4 nAChR could be another important target, since genetic studies show a possible role of the CHRNA5/A3/B4 gene cluster in the development of lung cancer which could lead to altered gene expression, but also to changed receptor function [38]. …”