Nicotine, through upregulating pro-survival signaling, cooperates with NNK to promote transformation.
Nicotine, through upregulating pro-survival signaling, cooperates with NNK to promote transformation.
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DOI：
10.1002/jcb.22392
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发表时间：
2010-01-01
影响因子：
4
通讯作者：
Chen, Chang Yan
中科院分区：
文献类型：
--
作者：
Nishioka, Takashi;Guo, Jinjin;Yamamoto, Daisuke;Chen, Lihua;Huppi, Petra;Chen, Chang Yan
吸烟是成千上万种化合物的混合物，其中许多是致癌物质，如nnk[4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone].。尼古丁作为香烟中的一种成瘾物质，已被证明可以促进非神经细胞的生长。目前尚不清楚尼古丁在肿瘤形成过程中如何与烟草相关的致癌物合作。在这里，通过尼古丁和NNK的同时处理，我们研究了这两种化合物的协同作用对各种不同的肺上皮(RLE)或癌细胞(LKR)细胞生长和凋亡的影响。我们证明，短期尼古丁暴露适度激活有丝分裂信号通路(如PKC、ERK和Akt)，对顺铂介导的细胞凋亡的保护作用一般。相反，NNK强烈刺激有丝分裂信号，使细胞对顺铂具有高耐药性。尼古丁预先结扎nAChR干扰NNK介导的丝裂原信号转导和对顺铂的耐药性，其程度与尼古丁单独作用相似。有趣的是，尼古丁或尼古丁加NNK作用一周后，Bcl2的表达增强，同时对顺铂诱导的细胞凋亡的抵抗力增强。相比之下，长期的NNK治疗对顺铂对细胞的保护作用很小。我们还发现，与NNK单独暴露相比，联合处理促进了更多的细胞以锚定独立的方式生长。因此，这些数据表明，尼古丁通过占据nAChR，似乎调制了NNK介导的信号，并持续地维持促进转化的亲生存活动。
Cigarette smoking is a mixture of thousands of compounds, many of which are carcinogens, such as NNK [4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone]. Nicotine, as an addictive substance in cigarette, has been shown to promote growth of non-neuronal cells. It is unclear how nicotine cooperates with tobacco-related carcinogens during tumorigenesis. Here, by concurrent treatment of nicotine and NNK, we investigate the effect of the cooperation of these two compounds on cell growth and apoptosis in various different lung epithelial (RLE) or cancer (LKR) cells. We demonstrated that short-term nicotine exposure moderately activated mitogenic signaling pathways (such as PKC, ERK and Akt) and a mediocre protection against cisplatin-mediated apoptosis. In contrast, NNK strongly stimulated mitogenic signaling and rendered the cells a high resistance to cisplatin. The pre-ligation of nAChR by nicotine interfered with NNK-mediated mitogenic signaling and resistance to cisplatin, the magnitude of which was similar as that exposed to nicotine alone. Interestingly, a week after the exposure to nicotine or nicotine plus NNK, Bcl-2 expression was augmented, accompanied with the increased resistance to cisplatin-induced apoptosis. In comparison, long-term NNK treatment provided very little protection of the cells from cisplatin. We also showed that the combination treatment promoted more cells to grow in an anchorage-independent fashion than NNK exposure alone. Thus, the data suggest that through occupying nAChR, nicotine appears to modulate NNK-mediated signaling and persistently sustain pro-survival activities to promote transformation.
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