Nicotine and 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone induce cyclooxygenase-2 activity in human gastric cancer cells: Involvement of nicotinic acetylcholine receptor (nAChR) and beta-adrenergic receptor signaling pathways

Toxicol Appl Pharmacol. 2008 Dec 1;233(2):254-61. doi: 10.1016/j.taap.2008.08.012. Epub 2008 Sep 6.


Induction of cyclooxygenase-2 (COX-2) associates with cigarette smoke exposure in many malignancies. Nicotine and its derivative, 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK), are the two important components in cigarette smoke that contributes to cancer development. However, the molecular mechanism(s) by which nicotine or NNK promotes gastric carcinogenesis remains largely unknown. We found that nicotine and NNK significantly enhanced cell proliferation in AGS cells that expressed both alpha7 nicotinic acetylcholine receptor (alpha7 nAChR) and beta-adrenergic receptors. Treatment of cells with alpha-bungarotoxin (alpha-BTX, alpha7nAChR antagonist) or propranolol (beta-adrenergic receptor antagonist) blocked NNK-induced COX-2/PGE(2) and cell proliferation, while nicotine-mediated cell growth and COX-2/PGE(2) induction can only be suppressed by propranolol, but not alpha-BTX. Moreover, in contrast to the dependence of growth promoting effect of nicotine on Erk activation, inhibitor of p38 mitogen-activated protein kinase (MAPK) repressed NNK-induced COX-2 upregulation and resulted in suppression of cell growth. In addition, nicotine and NNK mediated COX-2 induction via different receptors to modulate several G1/S transition regulatory proteins and promote gastric cancer cell growth. Selective COX-2 inhibitor (SC-236) caused G1 arrest and abrogated nicotine/NNK-induced cell proliferation. Aberrant expression of cyclin D1 and other G1 regulatory proteins are reversed by blockade of COX-2. These results pointed to the importance of adrenergic and nicotinic receptors in gastric tumor growth through MAPK/COX-2 activation, which may perhaps provide a chemoprevention strategy for cigarette smoke-related gastric carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism
  • Bungarotoxins / pharmacology
  • Carcinogens / toxicity*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Cyclin D1 / metabolism
  • Cyclooxygenase 2 / drug effects*
  • Cyclooxygenase 2 / metabolism
  • Dinoprostone / metabolism
  • Gene Expression Regulation / drug effects
  • Humans
  • Nicotine / toxicity*
  • Nitrosamines / toxicity*
  • Propranolol / pharmacology
  • Receptors, Adrenergic, beta / drug effects
  • Receptors, Adrenergic, beta / metabolism
  • Receptors, Nicotinic / drug effects
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / drug effects
  • Stomach Neoplasms / metabolism*
  • alpha7 Nicotinic Acetylcholine Receptor
  • p38 Mitogen-Activated Protein Kinases / drug effects
  • p38 Mitogen-Activated Protein Kinases / metabolism


  • Bungarotoxins
  • Carcinogens
  • Chrna7 protein, human
  • Nitrosamines
  • Receptors, Adrenergic, beta
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • Cyclin D1
  • Nicotine
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Propranolol
  • Cyclooxygenase 2
  • p38 Mitogen-Activated Protein Kinases
  • Dinoprostone