Nicotine promotes mammary tumor migration via a signaling cascade involving protein kinase C and CDC42.
Nicotine promotes mammary tumor migration via a signaling cascade involving protein kinase C and CDC42.
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DOI：
10.1158/0008-5472.can-08-0131
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Chen CY
中科院分区：
文献类型：
--
作者：
Guo J;Ibaragi S;Zhu T;Luo LY;Hu GF;Huppi PS;Chen CY
尼古丁是烟草中的主要成分之一，已被证明在吸烟者的血液中浓度很高。然而，尼古丁如何影响肿瘤发展的机制以及尼古丁是否为二手烟诱发的恶性肿瘤的潜在致癌物尚不完全清楚。在这里，我们研究了尼古丁促进人乳腺上皮样MCF10A或癌细胞MCF7肿瘤发生的信号通路。我们证明了人MCF10A和MCF7细胞都表达nAChR的四个亚基。尼古丁处理这些细胞可增强蛋白激酶Cα的活性，但不改变该激酶的表达水平。尼古丁还刺激[~3H]胸腺嘧啶核苷掺入这些细胞的基因组，并迫使血清饥饿的细胞进入细胞周期的S期，从而促进生长。重要的是，尼古丁处理后，MCF10A和MCF7细胞的流动性增强，这可以通过添加nAChR或PKC抑制剂来阻断。利用siRNA敲除或异位表达CDc42的实验表明，CDc42作为PKC的下游效应因子，在调节尼古丁介导的细胞迁移活动中起着至关重要的作用。总之，我们的发现表明，尼古丁通过与其受体相互作用，启动了涉及PKC和CDC42的信号级联反应，从而促进了乳腺上皮或肿瘤细胞的迁移。
Nicotine, one of major components in tobacco, has been shown to be at high concentrations in the blood stream of cigarette smokers. However, the mechanisms of how nicotine affects tumor development and whether nicotine is a potential carcinogen for malignancies induced by second-hand smoking are not fully understood yet. Here, we investigate the signaling pathways by which nicotine potentiates tumorigenesis in human mammary epithelial-like MCF10A or cancerous MCF7 cells. We demonstrate that human MCF10A and MCF7 cells both express four subunits of nAChR. The treatment of these cells with nicotine enhances the activity of protein kinase C (PKC) α without altering the expression level of this kinase. Nicotine also stimulates [3H]thymidine incorporation into the genome of these cells as well as forces serum-starved cells to enter S phase of the cell cycle, resulting of growth promotion. Importantly, upon nicotine treatment, the mobility of MCF10A and MCF7 cells are enhanced, which can be blocked by the addition of nAChR or PKC inhibitor. Experiments using siRNA knockdown or ectopic expression of cdc42 demonstrated that cdc42 functions as a downstream effector of PKC and is crucial in the regulation of nicotine-mediated migratory activity in the cells. Together, our findings suggest that nicotine, through interacting with its receptor, initiates a signaling cascade that involves PKC and cdc42, and consequently promotes migration in mammary epithelial or tumor cells.