The activation of STIM1 mediates S-phase arrest and cell death in paraquat induced acute lung intoxication
The activation of STIM1 mediates S-phase arrest and cell death in paraquat induced acute lung intoxication
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STIM1 的激活介导百草枯诱导的急性肺中毒中的 S 期停滞和细胞死亡
DOI：
10.1016/j.toxlet.2018.04.030
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发表时间：
2018-08-01
影响因子：
3.5
通讯作者：
Chen, Feng
中科院分区：
文献类型：
--
作者：
Fan, Hanting;Huang, Huijie;Chen, Feng
钙信号传导和氧化应激与多种应激条件下的细胞周期和细胞死亡紧密相关。近期研究表明，基质相互作用分子1（STIM1）是内质网钙传感器。然而，STIM1在百草枯（PQ）诱导的急性肺中毒中的调节机制及其作用仍不清楚。本研究的目的是探索PQ诱导的肺部急性中毒的分子和细胞机制，并进一步确定钙信号传导和活性氧（ROS）是否参与调节机制。我们的数据表明，PQ（500μM，24小时）诱导细胞内ROS产生，并增强了与STIM1激活相关的钙库操纵性钙内流（SOCE）活性。此外，PQ（500μM，24 - 48小时）导致细胞周期G1/S转换加速，然后停滞在S期。通过CRISPR - CAS9在16HBE细胞中敲除STIM1或抑制STIM1介导的SOCE激活，可减轻急性PQ处理导致的细胞死亡，这也通过调节细胞周期蛋白D1、p21、细胞周期蛋白A2和细胞周期蛋白依赖性激酶2（CDK2）的表达，缓解了S期的细胞积累。总之，STIM1在PQ诱导的急性肺损伤中的细胞周期停滞和细胞死亡中起重要作用，这可能为我们提供一个针对百草枯诱导中毒的新的潜在机会。
Calcium signaling and oxidative stress are tightly linked to cell cycle and cell death in response to a number of stress conditions. Recent study indicated that stromal interaction molecule 1 (STIM1) is the endoplasmic reticulum calcium sensor. However, the regulatory mechanisms and the role of STIM1 in paraquat (PQ)-induced acute lung intoxication remain elusive. The aim of this study was to explore the molecular and cellular mechanisms of PQ induced acute intoxication in the lung, and further determine whether calcium signaling and reactive oxygen species (ROS) participate in the regulatory mechanism. Our data demonstrated that PQ (500 mu M, 24 h) induced intracellular ROS production and enhanced store-operated calcium entry (SOCE) activity which is correlated to STIM1 activation. In addition, PQ (500 mu M, 24-48 h) caused accelerated cell cycle G1/S transition and then arrested in S phase. While knock-outing STIM1 by CRISPR-CAS9 in 16HBE or inhibiting STIM1 mediated SOCE activation ameliorated cell death caused by acute PQ treatment, which also leaded to alleviating the cell accumulation in S phase through the modulation the expression of cyclinD1, p21, cyclinA2 and CDK2. In conclusion, STIM1 plays an important role in PQ induced cell cycle arrest and cell death in acute lung injury, which may provide us a new potential opportunity to target paraquat induced intoxication.