Tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone suppresses a newly identified anti-tumor IGFBP-3/IGFBP-3R system in lung cancer cells

Lung Cancer. 2013 Jun;80(3):270-7. doi: 10.1016/j.lungcan.2013.02.016. Epub 2013 Mar 14.

Abstract

IGFBP-3 is a tumor suppressor whose expression is frequently suppressed in lung cancer. NNK, the most potent tobacco carcinogen, enhanced cell proliferation of BEAS-2B normal lung epithelial cells and concomitantly suppressed IGFBP-3 expression through DNA methylation. Decreased IGFBP-3 expression and elevated levels of phospho-Akt, phospho-p65-NF-κB, and cyclin D1 were detected in tobacco carcinogen-induced tumorigenic derivatives of BEAS-2B. Overexpression of IGFBP-3 in NNKA, one of the derivatives, suppressed NF-κB activity and induced apoptosis, which was hindered by knocking-down of endogenous IGFBP-3R, an IGFBP-3 specific receptor. These results suggest that NNK inhibits IGFBP-3 expression to abrogate anti-tumor actions of the IGFBP-3/IGFBP-3R system in smoking-induced lung cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Carcinogens / pharmacology
  • Carcinogens / toxicity
  • Cell Line, Tumor
  • Gene Expression Regulation, Neoplastic / drug effects
  • Humans
  • Insulin-Like Growth Factor Binding Protein 3 / genetics
  • Insulin-Like Growth Factor Binding Protein 3 / metabolism*
  • Lung Neoplasms / etiology
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Nitrosamines / pharmacology
  • Nitrosamines / toxicity*
  • Receptors, Cell Surface / genetics
  • Receptors, Cell Surface / metabolism*
  • Smoking / adverse effects
  • Tobacco Products

Substances

  • Carcinogens
  • IGFBP-3R protein, human
  • Insulin-Like Growth Factor Binding Protein 3
  • Nitrosamines
  • Receptors, Cell Surface
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone