Nicotinic acetylcholine receptors induce c-Kit ligand/Stem Cell Factor and promote stemness in an ARRB1/ β-arrestin-1 dependent manner in NSCLC.
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.
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA. Department of Hematology and Medical Oncology, Icahn School of Medicine at Mount Sinai, New York, USA.
Deepak
D
Perumal
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
Smitha
S
Pillai
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
Jonathan
J
Nguyen
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
Courtney
C
Schaal
Department of Anatomic Pathology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
Domenico
D
Coppola
Department of Tumor Biology, H. Lee Moffitt Cancer Center & Research Institute, Magnolia Drive, Tampa, FL, USA.
Srikumar P
SP
Chellappan
D000230:Adenocarcinoma / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D019390:Arrestins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002289:Carcinoma, Non-Small-Cell Lung / Q000378:metabolism / Q000401:mortality / Q000556:secondary*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000401:mortality / Q000556:secondary; D047369:Chromatin Immunoprecipitation; D050687:E2F1 Transcription Factor / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D004797:Enzyme-Linked Immunosorbent Assay; D020869:Gene Expression Profiling; D006801:Humans; D007124:Immunoenzyme Techniques; D008175:Lung Neoplasms / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D011978:Receptors, Nicotinic / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012907:Smoking; D019089:Stem Cell Factor / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins
C000605253:ARRB1 protein, human; D019390:Arrestins; D014408:Biomarkers, Tumor; D050687:E2F1 Transcription Factor; C493753:E2F1 protein, human; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D011978:Receptors, Nicotinic; D019089:Stem Cell Factor; D000071559:beta-Arrestin 1; D000071557:beta-Arrestins