Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma
Musashi-1 promotes chemoresistant granule formation by PKR/eIF2α signalling cascade in refractory glioblastoma
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DOI：
10.1016/j.bbadis.2018.02.017
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发表时间：
2018-05-01
影响因子：
6.2
通讯作者：
Chen, Ming-Teh
中科院分区：
文献类型：
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作者：
Chen, Hsiao-Yun;Lin, Liang-Ting;Chen, Ming-Teh
Musashi-1(MSI1)是一种RNA结合蛋白，不仅在神经干细胞中大量存在，而且在多种肿瘤组织中也广泛存在，并被报道为癌症进展的正向调节因子。越来越多的证据表明，PKR和eIF2α在刺激应激颗粒的形成以及随后的应激条件下的翻译调控中发挥着关键作用；然而，关于MSI1是否参与了这种PKR/eIF2α癌症干细胞增强机制，人们知之甚少。在这项研究中，我们证明了MSI1促进了人多形性胶质母细胞瘤(GBM)干细胞，并在暴露于亚致死压力时增强了化疗耐药性。MSI1的过度表达在减轻药物诱导的细胞死亡方面起到保护作用，从而促进三氧化二砷(ATO)诱导的化疗耐药应激颗粒(SGS)的形成。SG组分，如PKR和eIF2α，主要被激活和组装，而ATO参与。激活的PKR和eIF2α有助于干细胞基因的下游增强，从而促进GBM的进展。MSI1或PKR的沉默均可明显消除上述现象。综上所述，我们的发现表明，MSI1在应激颗粒的形成中起主导作用，该应激颗粒通过PKR/eIF2α信号级联反应对应激条件做出反应，从而赋予GBM中的癌症干细胞特性和耐化疗应激颗粒。
Musashi-1 (MSI1), one of the RNA-binding proteins, is abundantly found not only in neural stem cells but also in several cancer tissues and has been reported to act as a positive regulator of cancer progression. Growing evidence indicates that PKR and eIF2 alpha play pivotal roles in the stimulation of stress granule formation as well as in the subsequent translation modulation in response to stressful conditions; however, little is known about whether MSI1 is involved in this PKR/eIF2 alpha cancer stem cell-enhancing machinery. In this study, we demonstrated that MSI1 promotes human glioblastoma multiforme (GBM) stem cells and enhances chemoresistance when exposed to sublethal stress. The overexpression of MSI1 leads to a protective effect in mitigating drug induced cell death, thus facilitating the formation of chemoresistant stress granules (SGs) in response to arsenic trioxide (ATO) treatment. SG components, such as PKR and eIF2 alpha, were dominantly activated and assembled, while ATO was engaged. The activated PKR and eIF2 alpha contribute to the downstream enhancement of stem cell genes, thereby promoting the progression of GBM. The silencing of MSI1 or PKR both obviously withdrew the phenomena. Taken together, our findings indicate that MSI1 plays a leading role in stress granule formation that grants cancer stem cell properties and chemoresistant stress granules in GBM, in response to stressful conditions via the PKR/eIF2 alpha signalling cascade.