Anti-inflammatory Effects of Atorvastatin by Suppressing TRAF3IP2 and IL-17RA in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment
Anti-inflammatory Effects of Atorvastatin by Suppressing TRAF3IP2 and IL-17RA in Human Glioblastoma Spheroids Cultured in a Three-dimensional Model: Possible Relevance to Glioblastoma Treatment
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DOI：
10.1007/s12035-017-0445-2
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发表时间：
2018-03-01
影响因子：
5.1
通讯作者：
Ai, Jafar
中科院分区：
文献类型：
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作者：
Bayat, Neda;Ebrahimi-Barough, Somayeh;Ai, Jafar
多形性胶质母细胞瘤(GBM)是一种原发的恶性脑肿瘤，其治疗靶点很少。免疫系统和胶质瘤之间的相互作用是一个重要因素，可能导致新的治疗方法来对抗胶质瘤。在这项研究中，我们研究了不同浓度的阿托伐他汀1、5和10mM对三维培养的胶质瘤球状细胞的抗炎和凋亡活性，表明复杂的体内微环境比简单的二维细胞培养更好地显示了这种复杂的体内微环境。从机制上深入了解IL-17RA、TRAF3IP2和凋亡基因在胶质瘤发生发展中的作用，可能为通过调控这一炎性轴治疗恶性肿瘤提供重要的途径。为了达到上述目的，在不同浓度的阿托伐他汀作用24和48h后，检测caspase-8、caspase-3、bcl2、TRAF3IP2和IL-17RA基因的表达。采用末端脱氧核苷酸转移酶介导的dUTP缺口末端标记法和细胞周期分析法检测细胞的凋亡和增殖情况。结果表明，阿托伐他汀对胶质瘤球体具有抗炎和诱导细胞凋亡的作用。阿托伐他汀可诱导caspase-3和caspase-8的表达，下调Bcl2、TRAF3IP2和IL-17RA的表达，以10 mU M浓度最为明显。这些效应是剂量依赖性的。其机制可能是通过IL-17RA与TRAF3IP2和NF-kappa B信号通路的相互作用来抑制炎症反应。最后，这些结果表明阿托伐他汀可以作为一种抗癌药物用于胶质母细胞瘤的治疗。
Glioblastoma multiform (GBM) is a primary malignant brain tumor with a few therapeutic targets available for it. The interaction between the immune system and glioma is an important factor that could lead to novel therapeutic approaches to fight glioma. In this study, we investigated in vitro anti-inflammatory and apoptotic activity of atorvastatin in different concentrations 1, 5, and 10 mu M on glioma spheroid cells cultured in a three-dimensional model in fibrin gel that indicate the complex in vivo microenvironment better than a simple two-dimensional cell culture. A mechanistic insight into the role of IL-17RA, TRAF3IP2, and apoptotic genes in progression of glioma could provide an important way for therapy of malignant tumors with manipulation of this inflammatory axis. To reach for these aims, after 24 and 48 h exposure with different concentrations of atorvastatin, caspase-8, caspase-3, Bcl-2, TRAF3IP2, and IL-17RA gene expression were assayed. Terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay and cell cycle assay were used for evaluating the cell apoptosis and proliferation. The results showed that atorvastatin has anti-inflammatory and apoptotic effects against glioma spheroids. Atorvastatin induced the expression of caspase-3 and caspase-8 and downregulated the expression of Bcl-2, TRAF3IP2, and IL-17RA especially at 10 mu M concentration. These effects are dose dependent. The most likely mechanisms are the inhibition of inflammation by IL-17RA interaction with TRAF3IP2 and NF-kappa B signaling pathway. Finally, these results suggest that atorvastatin could be used as an anti-cancer agent for glioblastoma treatment.