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首页> 外文期刊>International immunopharmacology >The nicotinic acetylcholine receptor-mediated reciprocal effects of the tobacco nitrosamine NNK and SLURP-1 on human mammary epithelial cells
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The nicotinic acetylcholine receptor-mediated reciprocal effects of the tobacco nitrosamine NNK and SLURP-1 on human mammary epithelial cells

机译：烟草亚硝胺NNK和SLURP-1对人乳腺上皮细胞的烟碱乙酰胆碱受体介导的相互作用

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Recent research has demonstrated that the nicotinergic signaling network of mammary epithelium can both mediate the physiological control of normal breast epithelial cells (BECs) and exhibit tumor-promoting effects on malignant BECs. Therefore, mammary nicotinic acetylcholine, (ACh) receptors (nAChRs) may become a specific target for novel anti-breast cancer therapies. Toward this goal, we investigated the difference in the ACh receptor repertoires between normal and malignant BECs, determined effects of nicotinic ligands on 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-dependent activation of ERK1/2 and tumorigenic transformation of MCF10A cells, and characterized reciprocal effects of NNK and SLURP (secreted mammalian Ly-6/urokinase plasminogen activator receptor related protein-1)-1 on the expression of nAChR subunits and several oncogenes and tumor-suppressing genes in BECs. Both the non-malignant MCF10A and malignant MCF7 breast cells expressed alpha 3, alpha 5, alpha 7, alpha 9, alpha 10, beta 1,beta 2, gamma, delta and epsilon nAChR subunits and M-1, M-3, M-4 and M-5 muscarinic receptor subtypes. The malignancy was associated with expression of alpha 1, alpha 4 and beta 4 im nAChR subunits and M-2 subtype. Malignant transformation of BECs was also associated with overexpression of alpha 7-, and alpha 9-made nAChRs. NNK upregulated ERK1/2 phosphorylation, stimulated expression of the gene encoding the tumor-promoter HGF, downregulated expression of the tumor suppressor gene CDKN2A, and induced tumorigenic transformation of MCF10A cells. Compared to the canonical nAChR antagonists, SLURP-1 showed the highest ability to abolish the nAChR-mediated effects of NNK in both cell-signaling and cell-transformation assays and reversed many effects of NNK on gene expression. SLURP-1 also markedly upregulated the tumor suppressor genes CDKN2B, RUNX3 and TP73. Altogether, the obtained results provided new insight into the molecular mechanisms of nAChR-mediated oncogenic effects of NNK on BECs and demonstrated the ability to abolish or reverse these effects by SLURP-1. (C) 2015 Elsevier B.V. All rights reserved.
机译：最近的研究表明，乳腺上皮的烟碱能信号网络既可以介导正常乳腺上皮细胞（BEC）的生理控制，又可以对恶性BEC发挥促肿瘤作用。因此，乳腺的烟碱乙酰胆碱（ACh）受体（nAChRs）可能成为新型抗乳腺癌治疗的特定靶标。为了实现这一目标，我们调查了正常和恶性BEC之间ACh受体组成的差异，确定了烟碱配体对4-（甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮（NNK）依赖性ERK1活化的影响/ 2和MCF10A细胞的致瘤转化，并表征了NNK和SLURP（分泌的哺乳动物Ly-6 /尿激酶纤溶酶原激活物受体相关蛋白-1）-1对nAChR亚基和一些癌基因和抑癌基因表达的相互影响BEC。非恶性MCF10A和恶性MCF7乳腺癌细胞均表达α3，α5，α7，α9，α10，β1，β2，γ，δ和εnAChR亚基以及M-1，M-3，M -4和M-5毒蕈碱受体亚型。恶性肿瘤与α1，α4和β4imnAChR亚基和M-2亚型的表达有关。 BEC的恶性转化还与alpha 7-和alpha 9-nAChRs的过表达有关。 NNK上调ERK1 / 2磷酸化，刺激编码肿瘤启动子HGF的基因表达，下调肿瘤抑制基因CDKN2A的表达，并诱导MCF10A细胞致瘤转化。与经典的nAChR拮抗剂相比，SLURP-1在细胞信号转导和细胞转化试验中显示出最高的能力来消除nNKhR介导的NNK的作用，并逆转了NNK对基因表达的许多作用。 SLURP-1还显着上调了肿瘤抑制基因CDKN2B，RUNX3和TP73。总之，获得的结果为nAChR介导的NNK对BEC的致癌作用的分子机制提供了新的见识，并证明了SLURP-1消除或逆转这些作用的能力。 （C）2015 Elsevier B.V.保留所有权利。

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