title: Mechanisms of tumor-promoting activities of nicotine in lung cancer: synergistic effects of cell membrane and mitochondrial nicotinic acetylcholine receptors.
abstract: BACKGROUND
  One of the major controversies of contemporary medicine is created by an increased consumption of nicotine and growing evidence of its connection to cancer, which urges elucidation of the molecular mechanisms of oncogenic effects of inhaled nicotine. Current research indicates that nicotinergic regulation of cell survival and death is more complex than originally thought, because it involves signals emanating from both cell membrane (cm)- and mitochondrial (mt)-nicotinic acetylcholine receptors (nAChRs). In this study, we elaborated on the novel concept linking cm-nAChRs to growth promotion of lung cancer cells through cooperation with the growth factor signaling, and mt-nAChRs - to inhibition of intrinsic apoptosis through prevention of opening of mitochondrial permeability transition pore (mPTP).
  
  
  METHODS
  Experiments were performed with normal human lobar bronchial epithelial cells, the lung squamous cell carcinoma line SW900, and intact and NNK-transformed immortalized human bronchial cell line BEP2D.
  
  
  RESULTS
  We demonstrated that the growth-promoting effect of nicotine mediated by activation of α7 cm-nAChR synergizes mainly with that of epidermal growth factor (EGF), α3 - vascular endothelial growth factor (VEGF), α4 - insulin-like growth factor I (IGF-I) and VEGF, whereas α9 with EGF, IGF-I and VEGF. We also established the ligand-binding abilities of mt-nAChRs and demonstrated that quantity of the mt-nAChRs coupled to inhibition of mPTP opening increases upon malignant transformation.
  
  
  CONCLUSIONS
  These results indicated that the biological sum of simultaneous activation of cm- and mt-nAChRs produces a combination of growth-promoting and anti-apoptotic signals that implement the tumor-promoting action of nicotine on lung cells. Therefore, nAChRs may be a promising molecular target to arrest lung cancer progression and re-open mitochondrial apoptotic pathways.
authors.affiliation: Department of Dermatology, University of California, 134 Sprague Hall, Irvine, CA, 92697, USA. olek.cherny@uci.edu.
authors.forename: Alex I
authors.initials: AI
authors.lastname: Chernyavsky
authors.affiliation: National Cancer Institute, Kiev, Ukraine. ishchepotin@gmail.com.
authors.forename: Igor B
authors.initials: IB
authors.lastname: Shchepotin
authors.affiliation: Department of Dermatology, University of California, 134 Sprague Hall, Irvine, CA, 92697, USA. vgalitov@uci.edu.
authors.forename: Valentin
authors.initials: V
authors.lastname: Galitovkiy
authors.affiliation: Department of Dermatology, University of California, 134 Sprague Hall, Irvine, CA, 92697, USA. sgrando@uci.edu.|Department of Biological Chemistry, University of California, 134 Sprague Hall, Irvine, CA, 92697, USA. sgrando@uci.edu.|Cancer Center and Research Institute, University of California, 134 Sprague Hall, Irvine, CA, 92697, USA. sgrando@uci.edu.
authors.forename: Sergei A
authors.initials: SA
authors.lastname: Grando
mesh_terms: D002461:Cell Line, Transformed; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism*; D004305:Dose-Response Relationship, Drug; D006801:Humans; D008175:Lung Neoplasms / Q000139:chemically induced* / Q000378:metabolism*; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism*; D009538:Nicotine / Q000378:metabolism* / Q000633:toxicity; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D011978:Receptors, Nicotinic; D009538:Nicotine