Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors
Mechanisms of growth-promoting and tumor-protecting effects of epithelial nicotinic acetylcholine receptors
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DOI：
10.1016/j.intimp.2015.05.033
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发表时间：
2015-11-01
影响因子：
5.6
通讯作者：
Grando, Sergei A.
中科院分区：
文献类型：
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作者：
Chernyavsky, Alex I.;Shchepotin, Igor B.;Grando, Sergei A.
虽然尼古丁作为致癌物的作用是有争议的，但人们普遍认为它通过促进突变细胞克隆的生长和存活并保护它们免受化疗和放疗诱导的细胞凋亡而导致癌症。在细胞膜（cm）上，烟碱乙酰胆碱（ACh）受体（nAChR）实现增殖和存活基因的上调。尼古丁还可以渗透细胞并激活线粒体（mt）-nAChR，这与抑制线粒体渗透性转换孔（mPTP）开放偶联，从而防止细胞凋亡。在这项研究中，我们试图确定主要机制介导的肿瘤促进活动的尼古丁引起的激活cm和mt-nAChR在口腔癌细胞和肺癌细胞，SCC 25和SW 900，分别。发现激活的cm-nAChR分别通过α 7和β 2 nAChR亚基与EGF和VEGEF的受体形成复合物，而激活的mt-nAChR通过α 7和β 4亚基与线粒体内蛋白酶PI 3 K和Src物理相关。这分别与细胞周期蛋白D1的表达上调/ERK 1/2的激活和mPTP开放的抑制有关，以及与细胞增殖上调和对H2 O2诱导的细胞凋亡的抵抗有关。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（如ACh）如何调节另一种生物介质（如生长因子）的活性，反之亦然。mt-nAChRs与mPTP开放调节的功能偶联的建立提供了尼古丁依赖性保护细胞免于死亡的新机制。尼古丁促进肿瘤活性的这种新机制的进一步阐明应该具有强烈的翻译影响，因为神经元nAChR可能提供一种新的分子靶点，以预防，逆转或延缓尼古丁相关和不相关癌症的进展。(C)2015 Elsevier B. V.版权所有。
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.