The role of STIM1 in the Cr(vi)-induced [Ca2+]i increase and cell injury in L-02 hepatocytes.
The role of STIM1 in the Cr(vi)-induced [Ca2+]i increase and cell injury in L-02 hepatocytes.
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DOI：
10.1039/c6mt00204h
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发表时间：
2016-12
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影响因子：
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通讯作者：
Xing Yi;Yujing Zhang;Cai-gao Zhong;X. Zhong;F. Xiao
中科院分区：
文献类型：
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作者：
Xing Yi;Yujing Zhang;Cai-gao Zhong;X. Zhong;F. Xiao
六价铬是一种很强的细胞毒素和致癌物。近年来，饮用水中六价铬污染已成为一个具有重大公共卫生意义的世界性问题，因此对六价铬致肝毒性的研究倍受关注。细胞内钙离子浓度([Ca~(2+)]i)在铬(VI)暴露后升高，但涉及钙稳态失衡的确切机制尚不清楚。本研究利用钙离子通道拮抗剂2-氨基乙氧基二苯基硼酸酯(2-APB)、小分子干扰RNA对基质相互作用分子1(si-STIM1)和抗氧化剂N-乙酰半胱氨酸(NAC)的作用，发现铬(VI)可引起细胞内[Ca~(2+)]i升高、细胞活力丧失和转氨酶(AST/ALT)漏出，而2-APB和si-STIM1均可抑制这一作用。NAC可显著减轻铬(VI)诱导的STIM1、磷酸化细胞外信号调节蛋白1和2(p-ERK1/2)、ERK1/2和核因子κB(NF-κB)的上调。通过使用ERK抑制剂U0126和NF-κB抑制剂吡咯烷二硫代氨基甲酸酯，我们证实STIM1可以被ERK和NF-κB调节，从而得出STIM1在铬(VI)诱导的细胞内钙离子浓度升高和细胞损伤中起作用。我们的研究结果为进一步揭示STIM1在六价铬肝毒性中的作用机制提供了新的思路，并可能为铬(六价铬)职业人群肝病防治提供实验线索。
Hexavalent chromium [Cr(vi)] is a potent cytotoxin and carcinogen. In recent years, drinking water contamination with Cr(vi) has become a worldwide problem of significant public health importance, thus much attention has been paid to the investigation of Cr(vi)-induced hepatotoxicity. The concentration of intracellular calcium ions ([Ca2+]i) was found to be increased after Cr(vi) exposure, but the exact underlying mechanisms involved in the Ca2+ homeostasis imbalance remain poorly characterized. In the present study, by utilizing the antagonist of store-operated calcium channels (SOCCs) 2-aminoethoxydiphenyl borate (2-APB), small interfering RNA against stromal interaction molecule 1 (si-STIM1) and antioxidant N-acetylcysteine (NAC), we found that Cr(vi) induces [Ca2+]i increase, cell viability loss and transaminase (AST/ALT) leakage, and that these could be suppressed by both 2-APB and si-STIM1. NAC significantly alleviated Cr(vi)-induced up-regulation of STIM1, phosphorylated-extracellular-signal-regulated kinases 1 and 2 (p-ERK1/2), ERK1/2 and nuclear factor κB (NF-κB). By utilizing the ERK inhibitor U0126 and the NF-κB inhibitor pyrrolidine dithiocarbamate (PDTC), we confirmed that STIM1 can be regulated by ERK and NF-κB. Thus we concluded that STIM1 plays a role in the Cr(vi)-induced [Ca2+]i increase and cell injury. Our current data provide new insights into the mechanisms of STIM1 function in Cr(vi)-induced hepatotoxicity, and may provide experimental clues for the prevention and treatment of liver diseases in the occupational population exposed to Cr(vi).