Inhibition of Heat Shock Protein Response Enhances PS-341-Mediated Glioma Cell Death
Inhibition of Heat Shock Protein Response Enhances PS-341-Mediated Glioma Cell Death
复制标题
抑制热激蛋白反应可增强 PS-341 介导的胶质瘤细胞死亡
DOI：
10.1245/s10434-011-1881-2
复制
发表时间：
2012-07-01
影响因子：
3.7
通讯作者：
Ye, Yuanzhu
中科院分区：
文献类型：
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作者：
Liu, Yaohua;Zheng, Tianhu;Ye, Yuanzhu
背景研究表明PS-341在体外通过JNK途径诱导胶质瘤细胞死亡。然而，通过PS-341抑制蛋白酶体复合物可以诱导热休克蛋白（HSPs）的表达，其赋予对细胞应激的潜在保护。在这项研究中，我们探讨是否诱导热休克蛋白可以削弱PS-341诱导的细胞死亡和是否抑制热休克蛋白可以增强PS-341诱导的胶质瘤细胞的细胞damage.MethodsHSP表达在胶质瘤细胞中的调节通过热休克蛋白抑制剂，亚致死热，或敲低热休克因子1（HSF1），然后PS-341诱导的细胞损伤通过不同的方法进行了检查。在HSF 1 +/+和HSF 1-/-细胞中也进行了类似的实验。结果PS-341处理胶质瘤细胞后，HSF 1介导的HSP 70表达上调。PS-341介导的细胞损伤可通过HSP抑制而显著增强。此外，HSP70的表达和HSF1的核定位更丰富的胶质瘤比在正常的脑tissues.ConclusionsOur结果表明，HSP70受损的PS-341诱导的胶质瘤细胞的细胞死亡。PS-341联合HSP70抑制剂或HSF1基因敲减可能成为治疗胶质瘤的一种新方法。
BackgroundPrevious study indicated that PS-341 induces cell death via JNK pathway in vitro in glioma. However, suppressing proteasome complex by PS-341 may induce expression of heat shock proteins (HSPs), which confer potential protection against cellular stress. In this study, we explored whether induction of HSPs could impair PS-341-induced cell death and whether inhibition of HSPs could enhance cell damage induced by PS-341 in glioma cells.MethodsHSP expression in glioma cells was modulated by HSP inhibitor, sublethal heat, or knockdown of heat shock factor1 (HSF1), then PS-341-induced cell damage was examined by different methods. Similar experiments were also performed in HSF1+/+ and HSF1–/– cells. HSP70 expression and HSF1 nuclear localization were compared between glioma and normal brain tissues.ResultsHSP level was upregulated mediated by HSF1 when glioma cells were treated with PS-341. PS-341-mediated cell damage could be significantly augmented by HSP inhibition. Furthermore, HSP70 expression and HSF1 nuclear localization were much more abundant in gliomas than in normal brain tissues.ConclusionsOur results demonstrated that HSP70 impaired cell death induced by PS-341 in glioma cells. Administration of PS-341 in combination with either HSP70 inhibitor or HSF1 knockdown may act as a new approach to treatment of glioma.