Abstract
Lung cancer remains the leading cause of cancer-related deaths worldwide. β-arrestin-1 (ARRB1), a scaffolding protein involved in the desensitization of signals arising from activated G-protein-coupled receptors (GPCRs), has been shown to play a role in invasion and proliferation of cancer cells, including nicotine-induced proliferation of human non-small cell lung cancers (NSCLCs). In this study, we identified genes that are differentially regulated by nicotine in an ARRB1/β-arrestin-1 dependent manner in NSCLC cells by microarray analysis. Among the identified genes, SCF (Stem cell factor) strongly differentiated smokers from non-smokers in the Director's Challenge Set expression data and its high expression correlated with poor prognosis. SCF, a major cytokine is the ligand for the c-Kit proto-oncogene and was found to be over expressed in human lung adenocarcinomas, but not squamous cell carcinomas. Data presented here show that transcription factor E2F1 can induce SCF expression at the transcriptional level and depletion of E2F1 or ARRB1/β-arrestin-1 could not promote self-renewal of SP cells. These studies suggest that nicotine might be promoting NSCLC growth and metastasis by inducing the secretion of SCF, and raise the possibility that targeting signalling cascades that activate E2F1 might be an effective way to combat NSCLC.
Highlights
Lung cancer is the leading cause of cancer-related mortality accounting for approximately 15% of all cancer cases worldwide and has a 5-year survival rate of 15% [1]
We examined whether the expression of these genes correlated with smoking; it was found that only stem cell factor (SCF) strongly differentiated smokers from nonsmokers implying a potentially important role for this gene in lung carcinogenesis induced by smoking
Nicotine has been shown to induce epithelial-mesenchymal transition in a variety of cells as well, promoting tumor progression and metastasis [36]. All these effects of nicotine occur through nicotinic acetylcholine receptors, which are expressed on a wide variety of neuronal and non-neuronal cells
Summary
Lung cancer is the leading cause of cancer-related mortality accounting for approximately 15% of all cancer cases worldwide and has a 5-year survival rate of 15% [1]. In addition to promoting addiction to tobacco, exposure of non-neuronal cells to nicotine has been shown to promote cell proliferation and angiogenesis, enhancing tumor growth and metastasis [4,5,6]. Studies have shown that binding of nicotine to nAChRs triggers the synthesis and release of the stress neurotransmitters norepinephrine and epinephrine from lung adenocarcinoma cells and small airway epithelial cells. This stress-neurotransmitter-induced β-adrenergic receptor-initiates signaling via multiple pathways, including ERK, EGFR, Src and AKT resulting in proliferation and migration of these cells [11]. It has been reported that xenografts from lung adenocarcinomas are promoted in their growth via these β-adrenergic receptor pathways when the mice were exposed to social stress, resulting in elevated systemic levels of stress neurotransmitters [12]
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