Sevoflurane modulates the cancer stem cell-like properties and mitochondrial membrane potential of glioma via Ca2+-dependent CaMKII/JNK cascade
Sevoflurane modulates the cancer stem cell-like properties and mitochondrial membrane potential of glioma via Ca2+-dependent CaMKII/JNK cascade
复制标题
七氟醚通过钙依赖的CaMKII/JNK通路调节脑胶质瘤的肿瘤干细胞样特性和线粒体膜电位
DOI：
10.1016/j.lfs.2020.117675
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发表时间：
2020-07-15
期刊：
影响因子：
6.1
通讯作者：
Zhang, Lu
中科院分区：
文献类型：
--
作者：
Han, Xue-Chang;Zhang, Ya-Jie;Zhang, Lu
目的：脑胶质瘤是原发脑肿瘤死亡的主要原因。七氟醚在体外对肿瘤的生长有抑制作用。然而，七氟醚是否会影响胶质瘤干细胞的干性及其可能的分子机制尚未完全阐明。主要方法：观察七氟醚对胶质瘤细胞活力、增殖和侵袭能力以及体内肿瘤生长的影响。球体形成实验评价七氟醚对GSCs干性的影响。以细胞内/线粒体活性氧(ROS)水平和线粒体膜电位为指标评价七氟醚对线粒体功能的影响。Western blotting检测CaMKII/JNK信号通路中增殖相关蛋白、干性标志物和蛋白的表达水平。关键发现：七氟醚抑制胶质瘤细胞(U87 MG和U373 MG)的存活、增殖和侵袭能力。Western印迹结果显示，七氟醚可降低细胞增殖和侵袭相关蛋白的表达水平。七氟醚显著抑制GSCs的球体形成能力、茎干标志的表达水平和线粒体功能。此外，七氟醚可显著增加细胞内钙离子浓度，刺激CaMKII、JNK和IRS1的磷酸化。Ca~(2+)螯合剂BAPTA-AM与七氟醚协同抑制集落形成能力及增殖相关蛋白和茎标志的表达水平。此外，体内研究进一步证实了七氟醚通过钙依赖的CaMKII/JNK级联途径抑制肿瘤生长。意义：本研究证实七氟醚通过激活钙依赖的CaMKII/JNK级联途径抑制胶质瘤的发生，并调节肿瘤干细胞样特性和线粒体膜电位。
Aims: Gliomas are responsible for the majority of deaths from primary brain tumours. Sevoflurane showed inhibition effects on the tumor progression in vitro. However, whether sevoflurane could affect the stemness of glioma stem cells (GSCs) and the potential molecular mechanism have not been well elucidated.Main methods: Effects of sevoflurane on cell viability, proliferation and invasion ability of glioma cells as well as tumor growth in vivo were assessed. Sphere formation assay was performed to evaluate the effect of sevoflurane on the stemness of GSCs. Effects of sevoflurane on mitochondrial function was evaluated by intracellular/mitochondrial reactive oxygen species (ROS) level and mitochondrial membrane potential. Expression levels of proliferation-related proteins, stemness markers and proteins in CaMKII/JNK cascade were measured by Western blot.Key findings: Sevoflurane inhibited the viability, proliferation and invasion ability of glioma cells (U87MG and U373MG). Western blot showed that sevoflurane decreased the expression levels of proliferation and invasion-related proteins. Sphere formation ability of GSCs, expression levels of stemness markers and mitochondrial function were significantly suppressed by sevoflurane. Moreover, sevoflurane treatment significantly increased the Ca2+ concentration and stimulated phosphorylation of CaMKII, JNK and IRS1. Ca2+ chelator BAPTA-AM combined with sevoflurane synergistically inhibited colony forming ability and the expression levels of proliferation-related proteins and stemness markers. In addition, the in vivo study further confirmed that sevoflurane inhibited tumor growth via Ca2+-dependent CaMKII/JNK cascade.Significance: The present study demonstrated that sevoflurane inhibited glioma tumorigenesis and modulated the cancer stem cell-like properties and mitochondrial membrane potential via activation of Ca2+-dependent CaMKII/JNK cascade.