title: Recurrent exposure to nicotine differentiates human bronchial epithelial cells via epidermal growth factor receptor activation.
abstract: Cigarette smoking is the major preventable cause of lung cancer in developed countries. Nicotine (3-(1-methyl-2-pyrrolidinyl)-pyridine) is one of the major alkaloids present in tobacco. Besides its addictive properties, its effects have been described in panoply of cell types. In fact, recent studies have shown that nicotine behaves as a tumor promoter in transformed epithelial cells. This research focuses on the effects of acute repetitive nicotine exposure on normal human bronchial epithelial cells (NHBE cells). Here we show that treatment of NHBE cells with recurrent doses of nicotine up to 500 muM triggered cell differentiation towards a neuronal-like phenotype: cells emitted filopodia and expressed neuronal markers such as neuronal cell adhesion molecule, neurofilament-M and the transcription factors neuronal N and Pax-3. We also demonstrate that nicotine treatment induced NF-kB translocation to the nucleus, phosphorylation of the epidermal growth factor receptor (EGFR), and accumulation of heparin binding-EGF in the extracellular medium. Moreover, addition of AG1478, an inhibitor of EGFR tyrosine phosphorylation, or cetuximab, a monoclonal antibody that precludes ligand binding to the same receptor, prevented cell differentiation by nicotine. Lastly, we show that differentiated cells increased their adhesion to the extracellular matrix and their protease activity. Given that several lung pathologies are strongly related to tobacco consumption, these results may help to better understand the damaging consequences of nicotine exposure.
authors.affiliation: Centre for Applied Medical Research, School of Medicine, University of Navarra, Avenida Pío XII, 55, 31008 Pamplona, Spain.
authors.forename: Eva
authors.initials: E
authors.lastname: Martínez-García
authors.forename: Marta
authors.initials: M
authors.lastname: Irigoyen
authors.forename: Elena
authors.initials: E
authors.lastname: Ansó
authors.forename: Juan José
authors.initials: JJ
authors.lastname: Martínez-Irujo
authors.forename: Ana
authors.initials: A
authors.lastname: Rouzaut
mesh_terms: D001980:Bronchi / Q000187:drug effects*; D002448:Cell Adhesion / Q000187:drug effects; D002478:Cells, Cultured; D004847:Epithelial Cells / Q000187:drug effects; D066246:ErbB Receptors / Q000187:drug effects* / Q000502:physiology; D066257:Heparin-binding EGF-like Growth Factor; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D016328:NF-kappa B / Q000378:metabolism; D009538:Nicotine / Q000633:toxicity*; D021381:Protein Transport; D011978:Receptors, Nicotinic / Q000502:physiology; D015398:Signal Transduction
chemical_list: C587883:HBEGF protein, human; D066257:Heparin-binding EGF-like Growth Factor; D036341:Intercellular Signaling Peptides and Proteins; D016328:NF-kappa B; D011978:Receptors, Nicotinic; D009538:Nicotine; D066246:ErbB Receptors