© 2002 American Thoracic Society DOI: 10.1165/rcmb.4843 Cystic Fibrosis Transmembrane Conductance Regulator Modulates Neurosecretory Function in Pulmonary Neuroendocrine Cell-Related Tumor Cell Line ModelsDepartment of Paediatric Laboratory Medicine and Programme in Structural Biology and Biochemistry, Research Institute, The Hospital for Sick Children; and Departments of Laboratory Medicine & Pathobiology and Physiology, Faculty of Medicine, University of Toronto, Toronto, Canada Address correspondence to: Herman Yeger, Ph.D., Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, 555 University Avenue, Toronto, Ontario M5G 1X8 Canada. E-mail: hermie{at}sickkids.on.ca The pulmonary neuroendocrine cell (PNEC) system consists of solitary cells and distinctive cell clusters termed neuroepithelial bodies (NEB) localized in the airway epithelium. PNEC/NEB express a variety of bioactive substances, including amine (serotonin, 5HT) and neuropeptides. We have previously shown that NEB cells are O2 sensors expressing nicotinamide adenine diphosphate oxidase complex and O2 sensitive K+ channel. Recently, we demonstrated expression of functional cystic fibrosis transmembrane conductance regulator (CFTR) and Cl- conductances in NEB cells of rabbit neonatal lung. Because PNEC/NEB are sparsely distributed and difficult to study in native lung, we investigated small-cell lung carcinoma (SCLC) and carcinoid tumor cell lines (tumor counterparts of normal PNEC/NEB) as models for PNEC/NEB. SCLC (H146, H345) and carcinoid (H727) cell lines express neuroendocrine cell markers, including chromogranin A, neural cell adhesion molecule (N-CAM), 5HT, and tryptophan hydroxylase. We report that H146, H345, and H727 express CFTR messenger RNA (reverse transcription polymerase chain reaction) and protein (immunoblotting) and possess functional CFTR Cl- conductance, demonstrated by an iodide efflux assay inhibitable by transfection with antisense CFTR. Using an immunoassay to quantitate 5HT secretion, we also show that downregulation of CFTR abolishes hypoxia-induced 5HT release, and reduces secretory response to high potassium. Our findings suggest that CFTR may modulate neurosecretory activity of PNEC/NEB possessing O2 sensor function. We propose that these tumor cell lines may be useful models for investigating the role of CFTR in PNEC/NEB functions in health and disease.
Abbreviations: cystic fibrosis pancreatic adenocarcinoma, CFPAC-1 • cystic fibrosis transmembrane conductance regulator, CFTR • neural cell adhesion molecule, N-CAN • neuroepithelial body, NEB • pulmonary neuroendocrine cells, PNEC • reverse transcription polymerase chain reaction, RT-PCR • small-cell lung carcinoma, SCLC • tryptophan hydroxylase, TH This article has been cited by other articles:
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