Arsenic-induced apoptosis in the p53-proficient and p53-deficient cells through differential modulation of NFkB pathway.
Arsenic-induced apoptosis in the p53-proficient and p53-deficient cells through differential modulation of NFkB pathway.
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DOI：
10.1016/j.fct.2018.06.053
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发表时间：
2018-08
期刊：
影响因子：
--
通讯作者：
Yu X
中科院分区：
文献类型：
--
作者：
Yin L;Yu X
砷是一种著名的环境致癌物和有效的化疗药物。然而，这种双重效应的潜在机制尚不完全清楚。本研究以小鼠P53+/+和P53−/−细胞为研究对象，研究了砷处理后细胞因子κB途径和促炎性细胞因子的变化。与P53+/+细胞相比，砷降低了P53−/−细胞的存活率，增加了细胞的凋亡率，这与SAPK/JNK、p38MAPK和AKT通路的激活有关。转录调控网络分析显示，砷可激活P53+/+细胞中的转录调控元件E2F、Egr1、TrP53、Stat6、Bcl6、Creb2和ATF4，而在P53−/−细胞中，砷处理改变了转录因子NFκB、PPARG、Creb2、ATF4和Egr1。我们观察了两种基因在处理后4h至24小时内磷酸化的核因子κB p65(p-NFκB p65)和磷酸化IKKαβ(p-IKKαβ)的动态变化，在p53κ细胞中，p-NFαβ和p-IKKαβ的表达显著降低，而在p53+/+细胞中，p-NFκB p65和p-IKKαβ的表达显著增加。我们的研究证实了砷对p5 3+/+或p5 3+/+和p5 3+/+细胞中的NFκB通路的不同调节作用，这种对p5 3+/+和p5 3−/−细胞死亡机制不同的观察可能与砷具有致癌和化疗双重作用的独特能力有关。
Arsenic is a well-known environmental carcinogen and an effective chemotherapeutic agent. The underlying mechanism of this dual-effect, however, is not fully understood. In this study, we applied mouse p53+/+ and p53−/− cells to examine the NFκB pathway and proinflammatory cytokines after arsenic treatment. Arsenic reduced cell viability and increased more apoptosis in the p53−/− cells as compared to p53+/+ cells, which was correlated with activation of SAPK/JNK, p38 MAPK, and AKT pathways. A transcriptional regulatory network analysis revealed that arsenic activated transcription regulatory elements E2F, Egr1, Trp53, Stat6, Bcl6, Creb2 and ATF4 in the p53+/+ cells, while in the p53−/− cells, arsenic treatment altered transcription factors NFκB, Pparg, Creb2, ATF4, and Egr1. We observed dynamic changes in phosphorylated NFκB p65 (p-NFκB p65) and phosphorylated IKKαβ ( p-IKKαβ) in both genotypes from 4h to 24h after treatment, significant decreases of p-NFκB p65 and p-IKKαβ in the p53−/− cells, whereas increases of p-NFκB p65 and p-IKKαβ were observed in the p53+/+ cells. Our study confirmed the differential modulation of NFκB pathway by arsenic in the p53+/+ or p53−/− cells and this observation of the differential mechanism of cell death between the p53+/+ and p53−/− cells might be linked to the unique ability of arsenic to act as both a carcinogen and a chemotherapeutic agent.
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