Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas
Dissection of mitogenic and neurodegenerative actions of cystine and glutamate in malignant gliomas
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DOI：
10.1038/onc.2010.391
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发表时间：
2011-01-01
期刊：
影响因子：
8
通讯作者：
Hahnen, E.
中科院分区：
文献类型：
--
作者：
Savaskan, N. E.;Seufert, S.;Hahnen, E.
恶性胶质瘤是人类最具侵袭性和致命性的肿瘤之一。胶质瘤的一个特征是它们快速增殖和破坏重要的脑组织，在这个过程中，胶质瘤细胞过度释放谷氨酸占据中心地位。通过离子型谷氨酸受体拮抗谷氨酸信号的药理作用可延缓体内胶质瘤的进展，提示胶质瘤细胞释放谷氨酸是胶质瘤快速生长的先决条件。谷氨酸被认为以自分泌或旁分泌的方式促进胶质瘤细胞的增殖，特别是通过激活(RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic酸水合物(AMPA)亚型的谷氨酸受体。在这里，我们剖析了谷氨酸分泌在胶质瘤进展中的作用。胶质瘤细胞通过氨基酸逆向转运体系统X-c(-)释放谷氨酸，这一过程与半胱氨酸的掺入有机械联系。我们发现，通过干扰X-c(-)系统的活性来干扰谷氨酸的分泌，可以单独依赖半胱氨酸抑制胶质瘤细胞的增殖，而谷氨酸本身在体外并不促进胶质瘤细胞的生长。AMPA受体激动剂和拮抗剂均不影响胶质瘤的体外生长。在分子水平上，AMPA不敏感与AMPA受体亚单位显著转录下调或完全编辑的GluR2亚单位过度表达一致，这两者都阻断了受体的活性。值得注意的是，抑制植入肿瘤的脑片中的AMPA受体可显著减缓肿瘤的进展，并减轻神经细胞的死亡，这表明谷氨酸促进胶质瘤进展的能力严格要求肿瘤微环境。在潜在的药物治疗方面，靶向系统X-c(-)的活性破坏了胶质瘤细胞的两个主要病理生理特性，即诱导兴奋性毒性神经细胞死亡和掺入快速增殖所需的胱氨酸。Oncogene(2011年)30，43-53；doi：10.1038/onc.2010.391；2010年8月30日在线发布
Malignant glioma represents one of the most aggressive and lethal human neoplasias. A hallmark of gliomas is their rapid proliferation and destruction of vital brain tissue, a process in which excessive glutamate release by glioma cells takes center stage. Pharmacologic antagonism with glutamate signaling through ionotropic glutamate receptors attenuates glioma progression in vivo, indicating that glutamate release by glioma cells is a prerequisite for rapid glioma growth. Glutamate has been suggested to promote glioma cell proliferation in an autocrine or paracrine manner, in particular by activation of the (RS)-alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid hydrate (AMPA) subtype of glutamate receptors. Here, we dissect the effects of glutamate secretion on glioma progression. Glioma cells release glutamate through the amino-acid antiporter system X-c(-), a process that is mechanistically linked with cystine incorporation. We show that disrupting glutamate secretion by interfering with the system X-c(-) activity attenuates glioma cell proliferation solely cystine dependently, whereas glutamate itself does not augment glioma cell growth in vitro. Neither AMPA receptor agonism nor antagonism affects glioma growth in vitro. On a molecular level, AMPA insensitivity is concordant with a pronounced transcriptional downregulation of AMPA receptor subunits or overexpression of the fully edited GluR2 subunit, both of which block receptor activity. Strikingly, AMPA receptor inhibition in tumor-implanted brain slices resulted in markedly reduced tumor progression associated with alleviated neuronal cell death, suggesting that the ability of glutamate to promote glioma progression strictly requires the tumor microenvironment. Concerning a potential pharmacotherapy, targeting system X-c(-) activity disrupts two major pathophysiological properties of glioma cells, that is, the induction of excitotoxic neuronal cell death and incorporation of cystine required for rapid proliferation. Oncogene (2011) 30, 43-53; doi: 10.1038/onc.2010.391; published online 30 August 2010