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 μM, 24 h) induced intracellular ROS production and enhanced store-operated calcium entry (SOCE) activity which is correlated to STIM1 activation. In addition, PQ (500 μM, 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.
Keywords: Acute lung injury; Cell cycle; Forensic toxicology; Paraquat; S-phase arrest; STIM1.
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