Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-Catenin Signaling
Cyclophilin A Maintains Glioma-Initiating Cell Stemness by Regulating Wnt/β-Catenin Signaling
复制标题
亲环蛋白 A 通过调节 Wnt/β-连环蛋白信号转导维持胶质瘤起始细胞干性。
DOI：
10.1158/1078-0432.ccr-17-0774
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发表时间：
2017-11-01
影响因子：
11.5
通讯作者：
Guo, Mian
中科院分区：
文献类型：
--
作者：
Wang, Guangzhi;Shen, Jia;Guo, Mian
目的：胶质瘤起始细胞（GIC）是胶质瘤干细胞样细胞，有助于胶质母细胞瘤（GBM）的发展，复发和耐化疗和放疗。它们最近已成为新的治疗策略的焦点。亲环素A（CypA）是属于肽基脯氨酰异构酶（PPIase）家族的细胞溶质蛋白，并且是免疫抑制药物环孢菌素A（CsA）的主要细胞内靶标。在这项研究中，我们调查CypA的功能和它的作用机制在GICs' development.Experimental设计：我们分析了原发性肿瘤和GDS数据库中的神经球之间CypA表达的差异，无论是之前还是之后GIC分化。本研究通过一系列实验探讨CypA在GIC干性、自我更新、增殖、放射抵抗中的作用及其机制。然后，我们设计了谷胱甘肽S-转移酶（GST）下拉和coimmunoprecipitation检测信号activity.Results：在这项研究中，我们证明，CypA促进GIC干性，自我更新，增殖和放射治疗抗性。从机制上讲，我们发现CypA结合β-连环蛋白并被募集到Wnt靶基因启动子。通过增加β-catenin和TCF 4之间的相互作用，CypA增强转录activity.Conclusions：我们的研究结果表明，CypA增强GIC干性，自我更新，并通过Wnt/β-catenin信号辐射抗性。由于CypA对GIC的促进作用，它是未来胶质瘤治疗的潜在靶点。(C)2017年AACR。
Purpose: Glioma-initiating cells (GIC) are glioma stem-like cells that contribute to glioblastoma (GBM) development, recurrence, and resistance to chemotherapy and radiotherapy. They have recently become the focus of novel treatment strategies. Cyclophilin A (CypA) is a cytosolic protein that belongs to the peptidyl-prolyl isomerase (PPIase) family and the major intracellular target of the immunosuppressive drug cyclosporin A (CsA). In this study, we investigate the functions of CypA and its mechanism of action in GICs' development.Experimental Design: We analyzed differences in CypA expression between primary tumors and neurospheres from the GDS database, both before and after GIC differentiation. A series of experiments was conducted to investigate the role of CypA in GIC stemness, self-renewal, proliferation, radiotherapy resistance, and mechanism. We then designed glutathione S-transferase (GST) pulldown and coimmunoprecipitation assays to detect signaling activity.Results: In this study, we demonstrated that CypA promotes GIC stemness, self-renewal, proliferation, and radiotherapy resistance. Mechanistically, we found that CypA binds beta-catenin and is recruited to Wnt target gene promoters. By increasing the interaction between b-catenin and TCF4, CypA enhances transcriptional activity.Conclusions: Our results demonstrate that CypA enhances GIC stemness, self-renewal, and radioresistance through Wnt/beta-catenin signaling. Due to its promotive effects on GICs, CypA is a potential target for future glioma therapy. (C) 2017 AACR.