Nicotinic acetylcholine receptors mediate lung cancer growth

Abstract

Ion channels modulate ion flux across cell membranes, activate signal transduction pathways, and influence cellular transport-vital biological functions that are inexorably linked to cellular processes that go awry during carcinogenesis. Indeed, deregulation of ion channel function has been implicated in cancer-related phenomena such as unrestrained cell proliferation and apoptotic evasion. As the prototype for ligand-gated ion channels, nicotinic acetylcholine receptors (nAChRs) have been extensively studied in the context of neuronal cells but accumulating evidence also indicate a role for nAChRs in carcinogenesis. Recently, variants in the nAChR genes CHRNA3, CHRNA5, and CHRNB4 have been implicated in nicotine dependence and lung cancer susceptibility. Here, we silenced the expression of these three genes to investigate their function in lung cancer. We show that these genes are necessary for the viability of small cell lung carcinomas (SCLC), the most aggressive type of lung cancer. Furthermore, we show that nicotine promotes SCLC cell viability whereas an α3β4-selective antagonist, α-conotoxin AuIB, inhibits it. Our findings posit a mechanism whereby signaling via α3/α5/β4-containing nAChRs promotes lung carcinogenesis.

Cholinergic Targets in Lung Cancer

“…Studies by Gardner et al also suggest a role for α3, α4 and α5 containing heteromeric receptors as shown by antagonist and shRNA studies [42]. Implication of a role for α5 receptors in lung cancer growth is also consistent with the reports that polymorphisms in the α3, α5, β4 nAChR gene locus are associated with increased risk of lung cancer [52].…”

Novel perspectives in cancer therapy: Targeting ion channels

“…Targeted channels are in color. related nAChRs impairs viability of small cell lung carcinoma cells (SCLC) in vitro (Improgo et al, 2013). Relatively ample evidence is available regrading NSCLC cells, especially involving the ␣7 subunit (e.g., Lam et al, 2007;Grozio et al, 2008;Paleari et al, 2009).…”

Nicotine induces resistance to erlotinib via cross-talk between α 1 nAChR and EGFR in the non-small cell lung cancer xenograft model

“…It has been shown that nicotine can promote the growth and metastasis of solid tumors and increase chemotherapeutic resistance by inducing cell proliferation, invasion, angiogenesis and evasion of apoptosis [10][11][12]. These effects are due to the activation of PI3K/AKT, ERK 1/2, MAPK, MEK, NFkB, ␤-arrestin-1, Scr kinase, RbRaf-1 pathways and Bcl-2 family members induced by nicotine [12][13][14][15][16][17][18][19][20][21][22].…”