Autocrine glutamate signaling promotes glioma cell invasion
Autocrine glutamate signaling promotes glioma cell invasion
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DOI：
10.1158/0008-5472.can-07-2034
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发表时间：
2007-10-01
期刊：
影响因子：
11.2
通讯作者：
Sontheimer, Harald
中科院分区：
文献类型：
--
作者：
Lyons, Susan A.;Chung, W. Joon;Sontheimer, Harald
恶性神经胶质瘤已被证明会释放谷氨酸，杀死周围的脑细胞，为肿瘤扩张创造空间。这种谷氨酸释放主要通过系统x（C）（-）发生，系统x（C）（-）是一种Na+非依赖性胱氨酸-谷氨酸交换剂。此外，我们在这里显示，释放的谷氨酸作为一个必不可少的自分泌/旁分泌信号，促进细胞侵袭。具体而言，当使用S-（4）-CPG或柳氮磺胺吡啶（均为系统x（C）（-）的强效阻断剂）抑制谷氨酸释放时，趋化侵袭和刮擦运动试验均显示出对细胞迁移的剂量依赖性抑制。这种抑制作用可以通过在2，抑制剂的持续存在下加入外源性谷氨酸（100 μ mol/L）来克服。当使用GYKI或Joro蜘蛛毒素阻断Ca 2+渗透性α-氨基-3-羟基-5-甲基异恶唑-4-丙酸受体（AMPA-R）时，迁移/侵袭也受到抑制，而CNQX无效。Ca 2+成像21实验表明，释放的谷氨酸激活Ca 2+可渗透的AMPA-R并诱导细胞内Ca 2+振荡，这对于细胞迁移至关重要。重要的是，神经胶质瘤细胞释放足够量的谷氨酸，以激活自身或邻近细胞上的AMPA-R，从而以自分泌和/或旁分泌方式起作用。系统x（C）-和适当的AMPA-R亚基在所有胶质瘤细胞系、患者来源的胶质瘤细胞和研究的急性患者活检组织中表达。此外，将人类神经胶质瘤异种移植到scid小鼠中的动物研究表明，与盐水处理的对照组相比，系统x（C）（-）介导的谷氨酸释放的慢性抑制导致肿瘤更小，侵袭性更低。这些数据表明，神经胶质瘤的侵袭是有效地中断抑制自分泌谷氨酸信号循环与临床批准的候选药物，柳氮磺胺吡啶，已经在手。
Malignant gliomas have been shown to release glutamate, which kills surrounding brain cells, creating room for tumor expansion. This glutamate release occurs primarily via system x(C)(-), a Na+ -independent cystine-glutamate exchanger. We show here, in addition, that the released glutamate acts as an essential autocrine/paracrine signal that promotes cell invasion. Specifically, chemotactic invasion and scrape motility assays each show dose-dependent inhibition of cell migration when glutamate release was inhibited using either S-(4)-CPG or sulfasalazine, both potent blockers of system x(C)(-). This inhibition could be overcome by the addition of exogenous glutamate (100 mu mol/L) in the continued presence of the 2, inhibitors. Migration/invasion was also inhibited when Ca2+ permeable alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid receptors (AMPA-R) were blocked using GYKI or Joro spider toxin, whereas CNQX was ineffective. Ca2+ imaging 21 experiments show that the released glutamate activates Ca2+ - permeable AMPA-R and induces intracellular Ca2+, oscillations that are essential for cell migration. Importantly, glioma cells release glutamate in sufficient quantities to activate AMPA-Rs on themselves or neighboring cells, thus acting in an autocrine and/or paracrine fashion. System x(C)- and the appropriate AMPA-R subunits are expressed in all glioma cell lines, patient-derived glioma cells, and acute patient biopsies investigated. Furthermore, animal studies in which human gliomas were xenographed into scid mice show that chronic inhibition of system x(C)(-) -mediated glutamate release leads to smaller and less invasive tumors compared with saline-treated controls. These data suggest that glioma invasion is effectively disrupted by inhibiting an autocrine glutamate signaling loop with a clinically approved candidate drug, sulfasalazine, already in hand.