Chronic exposure to estrogen and the tobacco carcinogen NNK cooperatively modulates nicotinic receptors in small airway epithelial cells
Chronic exposure to estrogen and the tobacco carcinogen NNK cooperatively modulates nicotinic receptors in small airway epithelial cells
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DOI：
10.1016/j.lungcan.2009.09.011
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发表时间：
2010-07-01
期刊：
影响因子：
5.3
通讯作者：
Schuller, Hildegard M.
中科院分区：
文献类型：
--
作者：
Al-Wadei, Hussein A. N.;Al-Wadei, Mohammed H.;Schuller, Hildegard M.
小气道上皮细胞源性腺癌是最常见的人类肺癌，在女性中尤为普遍。我们之前报道过，单剂量烟草致癌物质NNK通过β -1-肾上腺素能受体（β - 1-AR）下游的cAMP信号通路刺激永生化人小气道上皮细胞HPL1D的增殖，而雌激素增强了这一反应。在目前的研究中，我们发现γ -氨基丁酸（GABA）阻断了HPL1D细胞中NNK和雌激素的这种协同信号传导。NNK还刺激去甲肾上腺素的产生，这是由α 7烟碱乙酰胆碱受体（α 7nAChR）介导的，同时通过α 4nAChR的脱敏减少GABA的产生。长期暴露于NNK、雌激素或两者联合上调和致敏α 7nAChR，导致对激动剂的去甲肾上腺素能反应增强。同时，慢性NNK和雌激素通过使其调节α 4 β 2nAChR脱敏来抑制GABA的产生。这种刺激和抑制信号的选择性不平衡可能导致吸烟女性小气道源性腺癌的发生和发展。2009爱思唯尔爱尔兰有限公司版权所有。
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 (beta 1-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 alpha 7 nicotinic acetylcholine receptor (alpha 7nAChR), while reducing GABA production via desensitization of the alpha 4nAChR. Chronic exposure to NNK, estrogen or the combination of both upregulated and sensitized the alpha 7nAChR, 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 alpha 4 beta 2nAChR. This selective imbalance in stimulatory and inhibitory signaling may contribute to the development and progression of small airway-derived adenocarcinoma in women who smoke. (C) 2009 Elsevier Ireland Ltd. All rights reserved.