Nicotinic acetylcholine receptors induce c-Kit ligand/Stem Cell Factor and promote stemness in an ARRB1/ β-arrestin-1 dependent manner in NSCLC
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Deepak Perumal1,3, Smitha Pillai1, Jonathan Nguyen1, Courtney Schaal1, Domenico Coppola2 and Srikumar P. Chellappan1*
1 Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA
2 Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA
3 Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA
Srikumar P. Chellappan, email:
Keywords: Self-renewal, E2F1, non-small cell lung cancer, Rb
Received: July 03, 2014 Accepted: August 26, 2014 Published: August 27, 2014
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.
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