Functional role of beta-adrenergic receptors in the mitogenic action of nicotine on gastric cancer cells

Toxicol Sci. 2007 Mar;96(1):21-9. doi: 10.1093/toxsci/kfl118. Epub 2006 Sep 26.


We previously reported that nicotine promoted gastric cancer cell growth via upregulation of cyclooxygenase 2 (COX-2). In the present study, we further investigated whether beta-adrenoceptors, protein kinase C (PKC), and extracellular signal-regulated kinase-1/2 (ERK1/2) were involved in the modulation of COX-2 expression and cell proliferation by nicotine in AGS, a human gastric adenocarcinoma cell line. Results showed that nicotine dose dependently increased the phosphorylation of EKR1/2 and the expression of AP-1 subunits c-fos and c-jun. In this connection, the ERK1/2 inhibitor U0126 abrogated the upregulation of AP-1 and COX-2 as well as cell proliferation induced by nicotine. Moreover, nicotine induced the translocation of PKC-betaI from cytosol to membrane and increased the total levels of PKC expression. Inhibition of PKC by staurosporine attenuated nicotine-induced ERK1/2 phosphorylation and COX-2 expression. Furthermore, atenolol and ICI 118,551, a beta1- and beta2-adrenoceptor antagonist, respectively, reversed the stimulatory action of nicotine on the expression of PKC, ERK1/2 phosphorylation, and COX-2 together with cell proliferation. Collectively, these results suggest that nicotine stimulates gastric cancer cell growth through the activation of beta-adrenoceptors and the downstream PKC-betaI/ERK1/2/COX-2 pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adenocarcinoma / metabolism*
  • Adenocarcinoma / physiopathology
  • Adrenergic beta-Antagonists / pharmacology
  • Atenolol / pharmacology
  • Butadienes / pharmacology
  • Cell Line, Tumor
  • Cell Proliferation / drug effects*
  • Cyclooxygenase 2 / biosynthesis
  • Dose-Response Relationship, Drug
  • Enzyme Induction / drug effects
  • Extracellular Signal-Regulated MAP Kinases / metabolism
  • Humans
  • Membrane Proteins / biosynthesis
  • Mitogens / pharmacology*
  • Nicotine / pharmacology*
  • Nitriles / pharmacology
  • Phosphorylation / drug effects
  • Propanolamines / pharmacology
  • Protein Kinase C / metabolism
  • Protein Kinase C beta
  • Protein Kinase Inhibitors / pharmacology
  • Protein Transport / drug effects
  • Receptors, Adrenergic, beta / drug effects*
  • Receptors, Adrenergic, beta / metabolism
  • Signal Transduction / drug effects*
  • Staurosporine / pharmacology
  • Stomach Neoplasms / metabolism*
  • Stomach Neoplasms / physiopathology
  • Transcription Factor AP-1 / biosynthesis


  • Adrenergic beta-Antagonists
  • Butadienes
  • Membrane Proteins
  • Mitogens
  • Nitriles
  • Propanolamines
  • Protein Kinase Inhibitors
  • Receptors, Adrenergic, beta
  • Transcription Factor AP-1
  • U 0126
  • ICI 118551
  • Atenolol
  • Nicotine
  • Cyclooxygenase 2
  • PTGS2 protein, human
  • Protein Kinase C
  • Protein Kinase C beta
  • Extracellular Signal-Regulated MAP Kinases
  • Staurosporine