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

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 (β1-AR) and that estrogen enhances this response. In the current study we show that γ-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 α7 nicotinic acetylcholine receptor (α7nAChR), while reducing GABA production via desensitization of the α4nAChR. Chronic exposure to NNK, estrogen or the combination of both upregulated and sensitized the α7nAChR, 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 α4β2nAChR. This selective imbalance in stimulatory and inhibitory signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke.