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首页> 外文期刊>Cellular Signalling >Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions
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Proteasome inhibitors sensitize glioma cells and glioma stem cells to TRAIL-induced apoptosis by PKCε-dependent downregulation of AKT and XIAP expressions

机译：蛋白酶体抑制剂通过PKCε依赖性下调AKT和XIAP表达使神经胶质瘤细胞和神经胶质瘤干细胞对TRAIL诱导的凋亡敏感

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In this study we examined the effects of proteasome inhibitors on cell apoptosis in TRAIL-resistant glioma cells and glioma stem cells (GSCs). Treatment with proteasome inhibitors and TRAIL induced apoptosis in all the resistant glioma cells and GSCs, but not in astrocytes and neural progenitor cells. Since PKCε has been implicated in the resistance of glioma cells to TRAIL, we examined its role in TRAIL and proteasome inhibitor-induced apoptosis. We found that TRAIL did not induce significant changes in the expression of PKCε, whereas a partial decrease in PKCε expression was obtained by proteasome inhibitors. A combined treatment of TRAIL and proteasome inhibitors induced accumulation of the catalytic fragment of PKCε and significantly and selectively decreased its protein and mRNA levels in the cancer but not in normal cells. Overexpression of PKCε partially inhibited the apoptotic effect of the proteasome inhibitors and TRAIL, and the caspase-resistant PKCεD383A mutant exerted a stronger inhibitory effect. Silencing of PKCε induced cell apoptosis in both glioma cells and GSCs, further supporting its role in cell survival. TRAIL and the proteasome inhibitors decreased the expression of AKT and XIAP in a PKCε-dependent manner and overexpression of these proteins abolished the apoptotic effect of this treatment. Moreover, silencing of XIAP sensitized glioma cells to TRAIL. Our results indicate that proteasome inhibitors sensitize glioma cells and GSCs to TRAIL by decreasing the expression of PKCε, AKT and XIAP. Combining proteasome inhibitors with TRAIL may be useful therapeutically in the treatment of gliomas and the eradication of GSCs.
机译：在这项研究中，我们检查了蛋白酶体抑制剂对TRAIL耐药神经胶质瘤细胞和神经胶质瘤干细胞（GSC）细胞凋亡的影响。蛋白酶体抑制剂和TRAIL的治疗诱导了所有耐药胶质瘤细胞和GSC中的凋亡，但星形胶质细胞和神经祖细胞中却没有。由于PKCε与神经胶质瘤细胞对TRAIL的抗性有关，因此我们检查了它在TRAIL和蛋白酶体抑制剂诱导的细胞凋亡中的作用。我们发现TRAIL不会诱导PKCε表达的显着变化，而蛋白酶体抑制剂可使PKCε表达部分降低。 TRAIL和蛋白酶体抑制剂的联合治疗诱导了PKCε催化片段的积累，并显着和选择性地降低了癌中的蛋白质和mRNA水平，但在正常细胞中却没有。 PKCε的过表达部分抑制了蛋白酶体抑制剂和TRAIL的凋亡作用，而耐半胱天冬酶的PKCεD383A突变体发挥了更强的抑制作用。 PKCε沉默导致神经胶质瘤细胞和GSC中的细胞凋亡，进一步支持其在细胞存活中的作用。 TRAIL和蛋白酶体抑制剂以PKCε依赖性方式降低AKT和XIAP的表达，并且这些蛋白的过表达消除了该处理的凋亡作用。而且，使XIAP致敏的神经胶质瘤细胞对TRAIL沉默。我们的结果表明，蛋白酶体抑制剂通过降低PKCε，AKT和XIAP的表达使神经胶质瘤细胞和GSC对TRAIL敏感。将蛋白酶体抑制剂与TRAIL联合使用可能在治疗神经胶质瘤和根除GSC方面具有治疗作用。

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