Low-Dose Nicotine Activates EGFR Signaling via α5-nAChR and Promotes Lung Adenocarcinoma Progression

Abstract

Nicotine in tobacco smoke is considered carcinogenic in several malignancies including lung cancer. The high incidence of lung adenocarcinoma (LAC) in non-smokers, however, remains unexplained. Although LAC has long been less associated with smoking behavior based on previous epidemiological correlation studies, the effect of environmental smoke contributing to low-dose nicotine exposure in non-smoking population could be underestimated. Here we provide experimental evidence of how low-dose nicotine promotes LAC growth in vitro and in vivo. Screening of nicotinic acetylcholine receptor subunits in lung cancer cell lines demonstrated a particularly high expression level of nicotinic acetylcholine receptor subunit α5 (α 5-nAChR) in LAC cell lines. Clinical specimen analysis revealed up-regulation of α 5-nAChR in LAC tumor tissues compared to non-tumor counterparts. In LAC cell lines α 5-nAChR interacts with epidermal growth factor receptor (EGFR), positively regulates EGFR pathway, enhances the expression of epithelial-mesenchymal transition markers, and is essential for low-dose nicotine-induced EGFR phosphorylation. Functionally, low-dose nicotine requires α 5-nAChR to enhance cell migration, invasion, and proliferation. Knockdown of α 5-nAChR inhibits the xenograft tumor growth of LAC. Clinical analysis indicated that high level of tumor α 5-nAChR is correlated with poor survival rates of LAC patients, particularly in those expressing wild-type EGFR. Our data identified α 5-nAChR as an essential mediator for low-dose nicotine-dependent LAC progression possibly through signaling crosstalk with EGFR, supporting the involvement of environmental smoke in tumor progression in LAC patients.

Association between smoking status and brain metastasis intervals and the prognosis of brain metastasis in patients with non-small cell lung cancer

“…Speci cally, nicotine enhances α7-nAChR expression and promotes M2-type polarisation of microglia by interfering with EGFR signalling and STAT3 pathways, thereby promoting cancer cell progression and metastasis. This suggests that nicotine can reprogram the brain tumour microenvironment to promote tumour progression by activating its receptors [22].…”

Contribution of the α5 nAChR Subunit and α5SNP to Nicotine-Induced Proliferation and Migration of Human Cancer Cells

“…This result shows that nicotine controls the mRNA expression levels of these proteins via α5-containing nAChRs. Yet additional mechanistic studies are still needed to reveal whether activation of the α5 affects the activity of other signaling pathways/proteins known to be influenced by the expression of such nicotinic receptor subtype, e.g., the vascular endothelial growth factor (VEGF) and epidermal growth factor receptor (EGFR) [33,87].…”

Targeting acetylcholine signaling modulates persistent drug tolerance in EGFR-mutant lung cancer and impedes tumor relapse

“…Previous studies have demonstrated that ACh pathway may mediate de novo resistance to EGFR-TKIs (54)(55)(56)(57). To investigate the potential role of ACh pathway in de novo (acute) resistance, we performed cell viability assays at early time points (48 h and 72 h) through genetic and pharmacological inhibition of ACh pathway modulators.…”