Nongenomic β estrogen receptors enhance β1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(Methyinitrosamino)-1-(3-Pyridyl)-1-Butanone in human small airway epithelial cells
Nongenomic β estrogen receptors enhance β1 adrenergic signaling induced by the nicotine-derived carcinogen 4-(Methyinitrosamino)-1-(3-Pyridyl)-1-Butanone in human small airway epithelial cells
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DOI：
10.1158/0008-5472.can-07-0483
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发表时间：
2007-07-15
期刊：
影响因子：
11.2
通讯作者：
Schuller, Hildegard M.
中科院分区：
文献类型：
--
作者：
Majidi, Mourad;Al-Wadei, Hussein A.;Schuller, Hildegard M.
女性患肺腺癌的风险高于男性;然而，对此机制知之甚少。在肺腺癌细胞中，雌激素受体β（ER β）是主要形式。我们发现，17 β-雌二醇增强了肺腺癌起源的假定细胞，小气道上皮细胞（HPLD 1）的增殖，以响应尼古丁衍生的亚硝胺4-（甲基亚硝胺）-1-（3-吡啶基）-1-丁酮（NNK）。反相蛋白质微阵列结合蛋白质印迹法显示，NNK诱导ER β磷酸化，这种作用涉及刺激肾上腺素能受体β 1（β 1AR）。在瞬时转染的细胞中，β 1AR与ER β共沉淀，其随着NNK处理而增加。ER β增强NNK诱导的环AMP积累以及G α i介导的促分裂原活化蛋白激酶/细胞外信号调节激酶（ERK）1/2活化。β 1AR和ER β共表达协同激活NNK介导的ERK 1/2。ER β基因敲除以及显性负性Ras和Raf的共表达减少了NNK对ERK 1/2的刺激。而NNK在Thr（308）和Ser（473）处磷酸化Akt，ER β对此活性没有影响。荧光素酶报告基因分析表明，响应于NNK，ER 6刺激血清反应元件（SRE）的转录，但对雌激素反应元件（ERE）的活性具有非常小的影响。总之，ER β的磷酸化、对G α i蛋白的依赖性、ERK 1/2的活化以及SRE相对于经典ERE途径的优先靶向支持非基因组ER β在吸烟相关肺癌的发展中的作用。β 1AR和ER β信号之间的这种新的合作可能有助于女性肺腺癌的突出。
Women are at higher risk for the development of lung adenocarcinoma than men; however, the mechanisms responsible for this are poorly understood. in lung adenocarcinoma cells, the estrogen receptor beta (ER beta) is the predominating form. We found that 17 beta-estradiol enhanced proliferation of the putative cells of origin of lung adenocarcinoma, small airway epithelial cells (HPLD1), in response to the nicotine-derived nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK). Reverse-phase protein microarrays combined with Western blotting revealed that NNK induced phosphorylation of ER beta, an effect that involved stimulation of the adrenergic receptors beta 1 (beta 1AR). In transiently transfected cells, beta 1AR coprecipitated with ER beta, which increased with NNK treatment. ER beta enhanced NNK-induced cyclic AMP accumulation as well as G alpha i-mediated mitogen-activated protein kinase/extracetlular signal-regulated kinase (ERK) 1/2 activation. Coexpression of beta 1AR and ER beta activated NNK-mediated ERK1/2 cooperatively. ER beta gene knockdown, as well as coexpression of the dominant negative Ras and Raf, reduced stimulation of ERK1/2 by NNK. Whereas NNK phosphorylated Akt at Thr(308) and Ser(473), ER beta had no effect on this activity. Luciferase reporter assays showed that, in response to NNK, ER6 stimulated transcription of serum responsive element (SRE) but had a very small effect on the activity of estrogen responsive element (ERE). Together, the phosphorylation of ER beta, the dependence on G alpha i proteins, the activation of ERK1/2, and the preferential targeting of SRE over the classic ERE pathway support a role for nongenomic ER beta in the development of smoking-associated lung cancer. This novel cooperation between beta 1AR and ER beta signaling may contribute to the prominence of lung adenocarcinoma in women.