Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling.
Lithium enhances the antitumour effect of temozolomide against TP53 wild-type glioblastoma cells via NFAT1/FasL signalling.
复制标题
锂通过 NFAT1/FasL 信号传导增强替莫唑胺对 TP53 野生型胶质母细胞瘤细胞的抗肿瘤作用
DOI：
10.1038/bjc.2017.89
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发表时间：
2017-05-09
影响因子：
8.8
通讯作者：
Wu A
中科院分区：
文献类型：
--
作者：
Han S;Meng L;Jiang Y;Cheng W;Tie X;Xia J;Wu A
我们以前表明，活化T细胞核因子（NFAT）1/Fas配体（FasL）途径的激活诱导胶质瘤细胞死亡。锂（Li）是糖原合成酶激酶（GSK）-3的抑制剂，可激活NFAT 1/FasL信号传导。替莫唑胺（TMZ）抑制GSK-3并激活肿瘤蛋白（TP）53野生型（TP 53 wt）胶质瘤细胞中的Fas。本研究探讨TMZ和低剂量Li对TP 53 wt胶质瘤细胞的联合作用。在TP 53 wt U87和原代胶质瘤细胞和小鼠异种移植模型中检查TMZ和Li的组合作用。与1.2 mM Li的组合增强TP 53 wt胶质瘤细胞中TMZ诱导的细胞死亡，如通过神经球形成和凋亡测定所确定的。替莫唑胺联合Li处理抑制GSK-3活化，促进NFAT 1核转位，上调Fas/FasL表达。靶向敲低NFAT 1表达可阻断TMZ和Li通过FasL抑制诱导的细胞死亡。在体内，TMZ和Li联合治疗抑制了肿瘤生长，延长了荷瘤小鼠的生存期。然而，TMZ和Li的组合在TP 53 mut胶质瘤细胞中没有产生统计学显著的效果。替莫唑胺联合低剂量Li通过NFAT 1/FasL信号传导诱导TP 53 wt胶质瘤细胞死亡这代表了TP 53 wt胶质瘤治疗的潜在治疗策略。
We previously showed that activation of the nuclear factor of activated T cells (NFAT)1/Fas ligand (FasL) pathway induces glioma cell death. Lithium (Li) is an inhibitor of glycogen synthase kinase (GSK)-3 that activates NFAT1/FasL signalling. Temozolomide (TMZ) inhibits GSK-3 and activates Fas in tumour protein (TP)53 wild-type (TP53wt) glioma cells. The present study investigated the combinational effects of TMZ and low-dose Li on TP53wt glioma cells. The combined effect of TMZ and Li was examined in TP53wt U87 and primary glioma cells and a mouse xenograft model. Combination with 1.2 mM Li potentiated TMZ-induced cell death in TP53wt glioma cells, as determined by neurosphere formation and apoptosis assays. Temozolomide combined with Li treatment inhibited GSK-3 activation, promoted NFAT1 nuclear translocation and upregulated Fas/FasL expression. Targeted knockdown of NFAT1 expression blocked the induction of cell death by TMZ and Li via FasL inhibition. In vivo, combined treatment with TMZ and Li suppressed tumour growth and prolonged the survival of tumour-bearing mice. However, the combination of TMZ and Li did not produce a statistically significant effect in TP53mut glioma cells. Temozolomide combined with low-dose Li induces TP53wt glioma cell death via NFAT1/FasL signalling. This represents a potential therapeutic strategy for TP53wt glioma treatment.