Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion.
Pertussis Toxin Is a Robust and Selective Inhibitor of High Grade Glioma Cell Migration and Invasion.
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DOI：
10.1371/journal.pone.0168418
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gonias SL
中科院分区：
文献类型：
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作者：
Gilder AS;Wang L;Natali L;Karimi-Mostowfi N;Brifault C;Gonias SL
在高级别神经胶质瘤 (HGG) 中，正常大脑的广泛肿瘤细胞浸润通常无法确定手术切除或放疗的有效边缘。百日咳毒素 (PT) 是一种多聚体复合物，可灭活多种 Gi/o G 蛋白偶联受体 (GPCR)。尽管 GPCR 控制的调控事件具有广泛的连续性，但 PT 可能可用作治疗方法。我们已经证明尿激酶受体 (uPAR) 是 HGG 细胞迁移的主要驱动因素。 uPAR 启动的细胞信号传导需要 Gi/o GPCR、N-甲酰肽受体 2 (FPR2) 作为重要的辅助受体，因此对 PT 敏感。在此，我们证明 PT 强烈抑制三种独立的 HGG 样细胞系的迁移，这些细胞系表达 EGF 受体 (EGFR) 的突变形式 EGFRvIII，该细胞具有组成型活性。 PT也几乎完全阻断了HGG细胞侵入Matrigel的能力。在等效浓度范围（0.01~1.0 μg/mL）下，PT对细胞存活没有影响，仅影响一种细胞系的增殖。 HGG 细胞中 EGFRvIII 表达的中和（已知会激活 uPAR 启动的细胞信号传导）促进 HGG 细胞迁移。 EGFRvIII 中和诱导的 HGG 细胞迁移增加可通过沉默 FPR2 基因表达或用 PT 处理细胞来完全阻断。当 U87MG HGG 细胞作为悬浮神经球在无血清、补充生长因子的培养基中培养时，uPAR 表达增加。从神经球中分离出的 HGG 细胞迁移通过 Transwell 膜，且细胞接触不丢失；该过程被 PT 抑制>90%。 PT 还抑制 HGG 细胞波形蛋白的表达；波形蛋白与上皮间质转化和预后恶化有关。我们得出结论，PT 可能作为 HGG 细胞迁移和侵袭的选择性抑制剂。
In high grade glioma (HGG), extensive tumor cell infiltration of normal brain typically precludes identifying effective margins for surgical resection or irradiation. Pertussis toxin (PT) is a multimeric complex that inactivates diverse Gi/o G-protein coupled receptors (GPCRs). Despite the broad continuum of regulatory events controlled by GPCRs, PT may be applicable as a therapeutic. We have shown that the urokinase receptor (uPAR) is a major driver of HGG cell migration. uPAR-initiated cell-signaling requires a Gi/o GPCR, N-formyl Peptide Receptor 2 (FPR2), as an essential co-receptor and is thus, PT-sensitive. Herein, we show that PT robustly inhibits migration of three separate HGG-like cell lines that express a mutated form of the EGF Receptor (EGFR), EGFRvIII, which is constitutively active. PT also almost completely blocked the ability of HGG cells to invade Matrigel. In the equivalent concentration range (0.01–1.0 μg/mL), PT had no effect on cell survival and only affected proliferation of one cell line. Neutralization of EGFRvIII expression in HGG cells, which is known to activate uPAR-initiated cell-signaling, promoted HGG cell migration. The increase in HGG cell migration, induced by EGFRvIII neutralization, was entirely blocked by silencing FPR2 gene expression or by treating the cells with PT. When U87MG HGG cells were cultured as suspended neurospheres in serum-free, growth factor-supplemented medium, uPAR expression was increased. HGG cells isolated from neurospheres migrated through Transwell membranes without loss of cell contacts; this process was inhibited by PT by >90%. PT also inhibited expression of vimentin by HGG cells; vimentin is associated with epithelial-mesenchymal transition and worsened prognosis. We conclude that PT may function as a selective inhibitor of HGG cell migration and invasion.
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DOI：
10.1073/pnas.1113416108
发表时间：
2011-09-20
影响因子：
11.1
作者：
Hu, Jingjing;Jo, Minji;Gonias, Steven L.
通讯作者：
Gonias, Steven L.
影响因子：
2.8
作者：
Ksiazkiewicz, Magdalena;Gottfried, Eva;Kunz-Schughart, Leoni A.
通讯作者：
Kunz-Schughart, Leoni A.
影响因子：
5.6
作者：
Gonias SL;Hu J
通讯作者：
Hu J
影响因子：
2.1
作者：
Otto, T;Lümmen, G;Rübben, H
通讯作者：
Rübben, H
影响因子：
8
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