Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers.
Nicotine-mediated cell proliferation and tumor progression in smoking-related cancers.
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DOI：
10.1158/1541-7786.mcr-13-0541
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发表时间：
2014-01
期刊：
影响因子：
--
通讯作者：
Chellappan SP
中科院分区：
文献类型：
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作者：
Schaal C;Chellappan SP
烟草烟雾中含有多种致癌物质，包括苯并（a）芘、多环芳烃和烟草特有的亚硝胺。这些化合物中的大多数通过形成DNA加合物和产生活性氧来发挥其遗传毒性作用，导致重要基因如K-Ras和p53突变。此外，烟草特有的亚硝胺可激活烟碱乙酰胆碱受体（nAChR），并在一定程度上激活β-肾上腺素能受体（β-AR），促进细胞增殖。此外，已证明尼古丁（烟草烟雾的主要成瘾成分）可诱导细胞周期进展、血管生成以及肺癌和胰腺癌的转移。这些作用主要通过α7-nAChR发生，可能有β-AR和/或表皮生长因子受体（EGFR）的作用。本文将讨论尼古丁及其致癌衍生物如NNK（4-甲基亚硝胺基）-1-（3-吡啶基）-1-丁酮）和NNN（N-亚硝基去甲尼古丁）诱导细胞周期进程和促进肿瘤生长的分子机制。尼古丁通过nAChR诱导多种信号级联反应，包括MAPK/ERK通路、PI 3 K/AKT通路和JAK/STAT信号通路。此外，研究表明，nAChR激活以β-arrestin-1依赖的方式诱导Src激酶，导致Rb蛋白失活，并导致E2 F1调节的增殖基因表达。这种nAChR介导的信号传导事件增强细胞的增殖，并使它们对由各种试剂诱导的细胞凋亡具有抗性。这些观察结果突出了nAChRs在促进肿瘤生长和转移中的作用，并提高了靶向它们用于癌症治疗的可能性。
Tobacco smoke contains multiple classes of established carcinogens including benzo(a)pyrenes, polycyclic aromatic hydrocarbons, and tobacco specific nitrosamines. Most of these compounds exert their genotoxic effects by forming DNA adducts and generation of reactive oxygen species, causing mutations in vital genes like K-Ras and p53. In addition, tobacco specific nitrosamines can activate nicotinic acetylcholine receptors (nAChRs) and to a certain extent β-Adrenergic receptors (β-ARs), promoting cell proliferation. Further, it has been demonstrated that nicotine, the major addictive component of tobacco smoke, can induce cell cycle progression, angiogenesis, and metastasis of lung and pancreatic cancers. These effects occur mainly through the α7-nAChRs, with possible contribution from the β-ARs and/or epidermal growth factor receptors (EGFRs). This review article will discuss the molecular mechanisms by which nicotine and its oncogenic derivatives such as NNK (4-methylnitrosamino)-1-(3-pyridyl)-1-butanone) and NNN (N-nitrosonornicotine) induce cell cycle progression and promote tumor growth. A variety of signaling cascades are induced by nicotine through nAChRs, including the MAPK/ERK pathway, PI3K/AKT pathway and JAK/STAT signaling. In addition, studies have shown that nAChR activation induces Src kinase in a β-arrestin-1 dependent manner, leading to the inactivation of Rb protein and resulting in the expression of E2F1-regulated proliferative genes. Such nAChR-mediated signaling events enhance the proliferation of cells and render them resistant to apoptosis induced by various agents. These observations highlight the role of nAChRs in promoting the growth and metastasis of tumors and raise the possibility of targeting them for cancer therapy.