Chronic exposure to estrogen and the tobacco carcinogen NNK cooperatively modulates nicotinic receptors in small airway epithelial cells

Lung Cancer. 2010 Jul;69(1):33-9. doi: 10.1016/j.lungcan.2009.09.011. Epub 2009 Nov 5.


Small airway epithelial cell-derived adenocarcinoma is the most common human lung cancer and is particularly prevalent in women. We have previously reported that the proliferation of immortalized human small airway epithelial cells HPL1D is stimulated by a single dose of the tobacco carcinogen NNK via cAMP signaling downstream of the beta-1-adrenergic receptor (beta1-AR) and that estrogen enhances this response. In the current study we show that gamma-aminobutyric acid (GABA) blocks this cooperative signaling of NNK and estrogen in HPL1D cells. NNK additionally stimulated the production of noradrenaline, an effect mediated by the alpha7 nicotinic acetylcholine receptor (alpha7nAChR), while reducing GABA production via desensitization of the alpha4nAChR. Chronic exposure to NNK, estrogen or the combination of both upregulated and sensitized the alpha7nAChR, resulting in an enhanced noradrenergic response to agonist. At the same time, chronic NNK and estrogen suppressed the production of GABA by desensitizing its regulatory alpha4beta2nAChR. This selective imbalance in stimulatory and inhibitory signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carcinogens / toxicity*
  • Drug Synergism
  • Epithelial Cells / drug effects*
  • Epithelial Cells / metabolism
  • Epithelial Cells / pathology
  • Estrogens / pharmacology*
  • Female
  • Humans
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Lung Neoplasms / physiopathology
  • Nitrosamines / toxicity*
  • Norepinephrine / metabolism
  • Receptor Cross-Talk
  • Receptors, Nicotinic / metabolism
  • Signal Transduction / drug effects
  • Small Cell Lung Carcinoma / metabolism*
  • Small Cell Lung Carcinoma / pathology
  • Small Cell Lung Carcinoma / physiopathology
  • Smoking
  • Up-Regulation / drug effects
  • alpha7 Nicotinic Acetylcholine Receptor
  • gamma-Aminobutyric Acid / pharmacology


  • Carcinogens
  • Chrna7 protein, human
  • Estrogens
  • Nitrosamines
  • Receptors, Nicotinic
  • alpha7 Nicotinic Acetylcholine Receptor
  • nicotinic acetylcholine receptor alpha4 subunit
  • gamma-Aminobutyric Acid
  • 4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone
  • Norepinephrine