Nicotinic receptor-mediated action of tobacco nitrosamines on respiratory cells

Summary

Principal Investigator: SERGEI GRANDO
Abstract: [unreadable] DESCRIPTION (provided by applicant): Long-term Objective: To establish contribution of nicotinic acetylcholine receptors (nAChRs) expressed in respiratory cells to mediating the oncogenic action of the nicotine-derived nitrosamines and identify antidotes to the tobacco-related carcinogenesis. Rationale: Nicotine, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) and N'-nitrosonornicotine (NNN) can specifically bind to nAChRs and alter growth of pulmonary cells. Our preliminary studies indicate that nicotinic antagonists can block binding of NNK and NNN to pulmonary cells and abolish effects of these nitrosamines on cell proliferation, apoptosis and anchorage-independent growth. Working Hypotheses: functional inactivation of nAChRs can: 1) abolish the oncogenic effects of NNK and NNN in in vitro and in vivo models of lung tumorigenesis; and 2) prevent alterations in the cholinergic receptor structure and function in respiratory cells. Specific Aims: to determine: 1) the roles for lung nAChRs in mediating oncogenic effects of NNK and NNN in cultures of human bronchial epithelial BEP2D cells and A/J mice; and 2) alterations in the gene expression and ligand-binding abilities of cholinergic receptors in the exposed respiratory cells, and tumors in mice. Methodology: To assure accurate "assignment" of the specific nAChR subtypes to a particular carcinogen, we will use overlapping approaches to abolish the effects of NNK and NNN. We will identify the nAChR- selective drug, small interfering RNA, or antisense oligonucleotides, that can abolish tumor-inducing activities of test nitrosamines. Significance: The results will provide crucial information for identifying the focus of future research toward elucidation of the role of specific nAChR subtypes in tobacco-related carcinogenesis and lung cancer chemoprevention. Description: The proposed research elaborates a novel paradigm of receptor-mediated action of tobacco carcinogens on target cells, and a well-substantiated hypothesis that an increased frequency of lung cancer in former smokers results from nicotine-induced alterations of binding to and signaling within the lung cells of the local hormone acetylcholine. The proposed studies will establish the role for each nAChR subtype involved in the process of malignant transformation of respiratory in response to the tobacco-specific nitrosamines. These findings will open a door for future mechanistic studies of the intracellular signaling pathways mediating the carcinogenic and tumor-promoting actions of tobacco nitrosamines. [unreadable] [unreadable] [unreadable]
Funding Period: 2006-09-11 - 2010-06-30
more information: NIH RePORT

Top Publications

  1. pmc Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors
    Alexander I Chernyavsky
    Institute for Immunology, University of California, Irvine, CA 92697, USA
    Int Immunopharmacol 10:308-15. 2010
  2. pmc Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases
    Alexander I Chernyavsky
    Department of Dermatology, University of California, Irvine, California 92697, USA
    Am J Physiol Cell Physiol 299:C903-11. 2010
  3. pmc SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes
    Juan Arredondo
    Department of Dermatology, University of California, Davis, CA 95816, USA
    Life Sci 80:2243-7. 2007
  4. pmc Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytes
    Juan Arredondo
    Department of Dermatology, University of California, Davis, USA
    Life Sci 80:2191-4. 2007
  5. pmc Overexpression of SLURP-1 and -2 alleviates the tumorigenic action of tobacco-derived nitrosamine on immortalized oral epithelial cells
    Juan Arredondo
    Department of Dermatology, University of California at Irvine, Irvine, CA 92697, USA
    Biochem Pharmacol 74:1315-9. 2007
  6. ncbi Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors
    Sergei A Grando
    Department of Dermatology, University of California Irvine 92697, USA
    J Pharmacol Sci 106:174-9. 2008
  7. ncbi Receptor-mediated tobacco toxicity: acceleration of sequential expression of alpha5 and alpha7 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smoke
    Juan Arredondo
    Department of Dermatology, University of California, Irvine, C340 Medical Sciences I, Irvine, CA 92697, USA
    FASEB J 22:1356-68. 2008
  8. ncbi Structure and function of the nicotinic arm of acetylcholine regulatory axis in human leukemic T cells
    A I Chernyavsky
    Center for Immunology and Departments of Dermatology and Biological Chemistry, University of California, Irvine, CA, USA
    Int J Immunopathol Pharmacol 22:461-72. 2009
  9. pmc Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity
    Alexander I Chernyavsky
    Department of Dermatology, University of California, Irvine, California 92697, USA
    J Biol Chem 284:22140-8. 2009

Scientific Experts

  • SERGEI GRANDO
  • Juan Arredondo
  • Alexander I Chernyavsky
  • Valentin Galitovskiy
  • Jing Qian
  • A I Chernyavsky
  • David L Jolkovsky
  • Kent E Pinkerton
  • Maryna Skok
  • J Arredondo
  • V Galitovskiy
  • J Qian
  • Alex I Chernyavsky

Detail Information

Publications9

  1. pmc Auto/paracrine control of inflammatory cytokines by acetylcholine in macrophage-like U937 cells through nicotinic receptors
    Alexander I Chernyavsky
    Institute for Immunology, University of California, Irvine, CA 92697, USA
    Int Immunopharmacol 10:308-15. 2010
    ..These findings offer a new insight on how nicotinic agonists control inflammation, thus laying a groundwork for the development of novel immunomodulatory therapies based on the nAChR subtype selectivity of nicotinic agonists...
  2. pmc Upregulation of nuclear factor-kappaB expression by SLURP-1 is mediated by alpha7-nicotinic acetylcholine receptor and involves both ionic events and activation of protein kinases
    Alexander I Chernyavsky
    Department of Dermatology, University of California, Irvine, California 92697, USA
    Am J Physiol Cell Physiol 299:C903-11. 2010
    ..Thus, there exists a previously not appreciated network of noncanonical auto/paracrine ligands of nAChR of the Ly-6 protein family, which merits further investigations...
  3. pmc SLURP-1 and -2 in normal, immortalized and malignant oral keratinocytes
    Juan Arredondo
    Department of Dermatology, University of California, Davis, CA 95816, USA
    Life Sci 80:2243-7. 2007
    ..These "proof-of-concept" preliminary results have salient clinical implications...
  4. pmc Receptor-mediated tobacco toxicity: alterations of the NF-kappaB expression and activity downstream of alpha7 nicotinic receptor in oral keratinocytes
    Juan Arredondo
    Department of Dermatology, University of California, Davis, USA
    Life Sci 80:2191-4. 2007
    ....
  5. pmc Overexpression of SLURP-1 and -2 alleviates the tumorigenic action of tobacco-derived nitrosamine on immortalized oral epithelial cells
    Juan Arredondo
    Department of Dermatology, University of California at Irvine, Irvine, CA 92697, USA
    Biochem Pharmacol 74:1315-9. 2007
    ..Thus, the anti-tumorigenic activities of SLURP-1 and -2 were demonstrated both in vitro and in vivo. The obtained results suggest that SLURP-like proteins may become useful for developing novel anti-cancer therapies...
  6. ncbi Basic and clinical aspects of non-neuronal acetylcholine: biological and clinical significance of non-canonical ligands of epithelial nicotinic acetylcholine receptors
    Sergei A Grando
    Department of Dermatology, University of California Irvine 92697, USA
    J Pharmacol Sci 106:174-9. 2008
    ....
  7. ncbi Receptor-mediated tobacco toxicity: acceleration of sequential expression of alpha5 and alpha7 nicotinic receptor subunits in oral keratinocytes exposed to cigarette smoke
    Juan Arredondo
    Department of Dermatology, University of California, Irvine, C340 Medical Sciences I, Irvine, CA 92697, USA
    FASEB J 22:1356-68. 2008
    ....
  8. ncbi Structure and function of the nicotinic arm of acetylcholine regulatory axis in human leukemic T cells
    A I Chernyavsky
    Center for Immunology and Departments of Dermatology and Biological Chemistry, University of California, Irvine, CA, USA
    Int J Immunopathol Pharmacol 22:461-72. 2009
    ....
  9. pmc Coupling of ionic events to protein kinase signaling cascades upon activation of alpha7 nicotinic receptor: cooperative regulation of alpha2-integrin expression and Rho kinase activity
    Alexander I Chernyavsky
    Department of Dermatology, University of California, Irvine, California 92697, USA
    J Biol Chem 284:22140-8. 2009
    ....