PI3K inhibitor combined with miR-125b inhibitor sensitize TMZ-induced anti-glioma stem cancer effects through inactivation of Wnt/β-catenin signaling pathway
PI3K inhibitor combined with miR-125b inhibitor sensitize TMZ-induced anti-glioma stem cancer effects through inactivation of Wnt/β-catenin signaling pathway
复制标题
PI3K抑制剂与miR-125b抑制剂联合通过灭活Wnt/β-catenin信号通路使TMZ诱导的抗神经胶质瘤干癌作用变得敏感
DOI：
10.1007/s11626-015-9931-x
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发表时间：
2015-11-01
影响因子：
2.1
通讯作者：
You, Yongping
中科院分区：
文献类型：
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作者：
Shi, Lei;Fei, Xifeng;You, Yongping
替莫唑胺（TMZ）是一种很有前途的治疗胶质母细胞瘤的化疗药物。然而，电阻发展迅速，频率高。胶质母细胞瘤干细胞（GSCs）对药物治疗产生耐药性被认为是关键因素之一。GSCs对TMZ的抗性机制尚不完全清楚。MicroRNAs （miRNAs）在肿瘤发生和耐药过程中发挥着重要作用。我们之前的研究表明，miR-125b是GSCs裂变所必需的，抑制miR-125b可以增强GSCs对TMZ的化学敏感性。近年来的研究表明，多种药物和上游因子通过PI3K/Akt通路起作用，抑制PI3K/Akt通路对GSCs的作用远大于非GSCs。在本研究中，我们发现PI3K抑制剂联合miR-125b抑制剂可显著增加tmz诱导的GSC增殖和侵袭性抑制。为了探索其潜在的机制，我们发现这种新的组合方案导致Wnt/ β -catenin通路失活的改变，该通路调节细胞凋亡、增殖、分化和代谢等一系列细胞活性。综上所示，我们的数据有力地支持PI3K抑制剂和miR-125b抑制剂通过靶向Wnt/ β -catenin信号通路，在赋予GSCs对TMZ的抗性方面发挥重要作用。
Temozolomide (TMZ) is a promising chemotherapeutic agent for treating glioblastomas. However, resistance develops quickly with a high frequency. Glioblastoma stem cells (GSCs) causing resistance to drug therapy were considered to be one of the key factors. The mechanisms underlying GSCs resistance to TMZ are not fully understood. MicroRNAs (miRNAs) have emerged to play important roles in tumorigenesis and drug resistance. Our previous studies showed that miR-125b was necessary for GSCs fission, and inhibition of which could enhance the chemosensitivity of GSCs to TMZ. Recent studies have evidence that a variety of drugs and upstream factors work through PI3K/Akt pathway, and the effects of PI3K/Akt pathway inhibition on GSCs were much more than non-GSCs. In this study, we found that PI3K inhibitor combined with miR-125b inhibitor caused a marked increase of TMZ-induced GSC proliferation and invasiveness inhibition. To explore the potential mechanism, we found that this novel combinatorial regimen leads to changes of inactivation of Wnt/beta-catenin pathway which regulates a series of cell activities including cell apoptosis, proliferation, differentiation, and metabolism. Taken together, our data strongly support an important role for PI3K inhibitor and miR-125b inhibitor on conferring GSCs resistance to TMZ through targeting Wnt/beta-catenin signaling pathway.