The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death.
The Inhibition of microRNA-128 on IGF-1-Activating mTOR Signaling Involves in Temozolomide-Induced Glioma Cell Apoptotic Death.
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DOI：
10.1371/journal.pone.0167096
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Chen KC
中科院分区：
文献类型：
--
作者：
Chen PH;Cheng CH;Shih CM;Ho KH;Lin CW;Lee CC;Liu AJ;Chang CK;Chen KC
替莫唑胺（TMZ）是咪唑四嗪系列的烷化剂，是临床治疗多形性胶质母细胞瘤（Glioblastoma multiforme）的一线化疗药物。微RNA是一种非编码小RNA，在转录后调节基因表达，参与胶质瘤的形成。然而，没有研究报道TMZ和miRNA基因调控之间的关系。我们研究了TMZ介导的miRNA谱及其诱导胶质瘤细胞死亡的分子机制。通过进行miRNA微阵列和生物信息学分析，我们观察到TMZ处理的U87 MG细胞中248个miRNA的表达发生了改变，包括5个显著上调和17个显著下调的miRNA。miR-128在不同胶质瘤细胞中的表达水平较低，并且与较差的存活率密切相关。TMZ处理显著上调miR-128表达。TMZ显著增强miR-128-1启动子活性，并通过c-Jun N末端激酶2/c-Jun途径转录调节miR-128水平。miR-128表达的过表达和敲低显著影响TMZ介导的细胞活力和凋亡相关蛋白的表达。此外，单独过表达miR-128通过caspase-3/9激活、聚（ADP核糖）聚合酶降解、活性氧产生、线粒体膜电位丧失和非保护性自噬形成增强胶质瘤细胞的凋亡死亡。最后，我们确定了哺乳动物雷帕霉素靶蛋白（mTOR）信号传导中的关键成员，包括mTOR、mTOR的雷帕霉素不敏感伴侣、胰岛素样生长因子1和PIK 3R 1，而不是PDK 1，是miR-128的直接靶基因。TMZ通过miR-128调节抑制mTOR信号传导。这些结果表明miR-128抑制的mTOR信号传导参与TMZ介导的细胞毒性。我们的研究结果可能会提供一个更好的理解TMZ参与胶质母细胞瘤的发展的细胞毒性机制。
Temozolomide (TMZ), an alkylating agent of the imidazotetrazine series, is a first-line chemotherapeutic drug used in the clinical therapy of glioblastoma multiforme, the most common and high-grade primary glioma in adults. Micro (mi)RNAs, which are small noncoding RNAs, post-transcriptionally regulate gene expressions and are involved in gliomagenesis. However, no studies have reported relationships between TMZ and miRNA gene regulation. We investigated TMZ-mediated miRNA profiles and its molecular mechanisms underlying the induction of glioma cell death. By performing miRNA microarray and bioinformatics analyses, we observed that expression of 248 miRNAs was altered, including five significantly upregulated and 17 significantly downregulated miRNAs, in TMZ-treated U87MG cells. miR-128 expression levels were lower in different glioma cells and strongly associated with poor survival. TMZ treatment significantly upregulated miR-128 expression. TMZ significantly enhanced miR-128-1 promoter activity and transcriptionally regulated miR-128 levels through c-Jun N-terminal kinase 2/c-Jun pathways. The overexpression and knockdown of miR-128 expression significantly affected TMZ-mediated cell viability and apoptosis-related protein expression. Furthermore, the overexpression of miR-128 alone enhanced apoptotic death of glioma cells through caspase-3/9 activation, poly(ADP ribose) polymerase degradation, reactive oxygen species generation, mitochondrial membrane potential loss, and non-protective autophagy formation. Finally, we identified that key members in mammalian target of rapamycin (mTOR) signaling including mTOR, rapamycin-insensitive companion of mTOR, insulin-like growth factor 1, and PIK3R1, but not PDK1, were direct target genes of miR-128. TMZ inhibited mTOR signaling through miR-128 regulation. These results indicate that miR-128-inhibited mTOR signaling is involved in TMZ-mediated cytotoxicity. Our findings may provide a better understanding of cytotoxic mechanisms of TMZ involved in glioblastoma development.
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影响因子：
4.9
作者：
Ananta, Jeyarama S.;Paulmurugan, Ramasamy;Massoud, Tank F.
通讯作者：
Massoud, Tank F.
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影响因子：
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作者：
Lin, Lina;Chen, Xulin;Jiang, Songshan
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影响因子：
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Terzis, AJ
影响因子：
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Godlewski, Jakub;Nowicki, Michal O.;Lawler, Sean
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Lawler, Sean
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作者：
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