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首页> 外文期刊>International immunopharmacology >Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors
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Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors

机译：上皮烟碱乙酰胆碱受体的生长促进和肿瘤保护作用的机制

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Although the role of nicotine as a carcinogen is debatable, it is widely accepted that it contributes to cancer by promoting growth and survival of mutated cell clones and protecting them from the chemo- and radiotherapy-induced apoptosis. On the cell membrane (cm), the nicotinic acetylcholine (ACh) receptors (nAChRs) implement upregulation of proliferative and survival genes. Nicotine also can permeate cells and activate mitochondrial (mt)-nAChRs coupled to inhibition of the mitochondrial permeability transition pore (mPTP) opening, thus preventing apoptosis. In this study, we sought to pin down principal mechanisms mediating the tumor-promoting activities of nicotine resulting from activation of cm- and mt-nAChRs in oral and lung cancer cells, SCC25 and SW900, respectively. Activated cm-nAChRs were found to form complexes with receptors for EGF and VEGEF via the alpha 7 and beta 2 nAChR subunits, respectively, whereas activated mt-nAChRs physically associated with the intramitochondrial protein ldnases PI3K and Src via the alpha 7 and beta 4 subunits. This was associated with upregulated expression of cyclin D1/activation of ERK1/2 and inhibition of mPTP opening, respectively, as well as upregulated proliferation and resistance to H2O2-induced apoptosis. The molecular synergy between cm-nAChRs and growth factor receptors helps explain how one biological mediator, such as ACh, can modulate activity of the other, such as a growth factor, and vice versa. Establishment of functional coupling of mt-nAChRs to regulation of mPTP opening provides a novel mechanism of nicotine-dependent protection from cell death. Further elucidation of this novel mechanism of tumor-promoting activities of nicotine should have a strong translational impact, because extraneuronal nAChRs may provide a novel molecular target to prevent, reverse, or retard progression of both nicotine-related and unrelated cancers. (C) 2015 Elsevier B.V. All rights reserved.
机译：尽管尼古丁作为致癌物的作用尚有争议，但人们普遍认为尼古丁通过促进突变细胞克隆的生长和存活并保护其免受化学和放射疗法诱导的细胞凋亡而有助于癌症。在细胞膜（cm）上，烟碱乙酰胆碱（ACh）受体（nAChRs）上调增殖和存活基因。尼古丁还可以渗透细胞并激活线粒体（mt）-nAChR，从而抑制线粒体通透性转换孔（mPTP）的开放，从而防止细胞凋亡。在这项研究中，我们试图确定介导分别由口腔和肺癌细胞SCC25和SW900中的cm-和mt-nAChRs激活引起的尼古丁促进肿瘤活动的主要机制。发现激活的cm-nAChRs分别通过alpha 7和beta 2 nAChR亚基与EGF和VEGEF受体形成复合物，而激活的mt-nAChRs通过alpha 7和beta 4亚基与线粒体内蛋白ldnases PI3K和Src物理相关。 。这分别与上调细胞周期蛋白D1 / ERK1 / 2的激活和抑制mPTP的开放有关，以及上调对H2O2诱导的细胞凋亡的增殖和抗性。 cm-nAChRs和生长因子受体之间的分子协同作用有助于解释一种生物介质（例如ACh）如何调节另一种介质（例如生长因子）的活性，反之亦然。 mt-nAChRs与mPTP开放调节功能偶联的建立提供了尼古丁依赖性保护免受细胞死亡的新机制。进一步阐明这种尼古丁促进肿瘤活动的新机制应该具有很强的翻译作用，因为神经外神经元nAChRs可能提供新的分子靶标，以预防，逆转或延迟尼古丁相关和无关癌症的发展。 （C）2015 Elsevier B.V.保留所有权利。

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