van Vuurden Dannis G, Yazdani Maryam, Bosma Ingeborg, Broekhuizen Aart J F, Postma Tjeerd J, Heimans Jan J, van der Valk Paul, Aronica Eleonora, Tannous Bakhos A, Würdinger Thomas, Kaspers Gertjan J L, Cloos Jacqueline
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
PLoS One. 2009 Jun 18;4(6):e5953. doi: 10.1371/journal.pone.0005953.
Glioblastoma multiforme (GBM) cells secrete large amounts of glutamate that can trigger AMPA-type glutamate receptors (AMPARs). This commonly results in Na(+) and Ca(2+)-permeability and thereby in excitotoxic cell death of the surrounding neurons. Here we investigated how the GBM cells themselves survive in a glutamate-rich environment.
In silico analysis of published reports shows down-regulation of all ionotropic glutamate receptors in GBM as compared to normal brain. In vitro, in all GBM samples tested, mRNA expression of AMPAR subunit GluR1, 2 and 4 was relatively low compared to adult and fetal total brain mRNA and adult cerebellum mRNA. These findings were in line with primary GBM samples, in which protein expression patterns were down-regulated as compared to the normal tissue. Furthermore, mislocalized expression of these receptors was found. Sequence analysis of GluR2 RNA in primary and established GBM cell lines showed that the GluR2 subunit was found to be partly unedited.
Together with the lack of functional effect of AMPAR inhibition by NBQX our results suggest that down-regulation and afunctionality of AMPARs, enable GBM cells to survive in a high glutamate environment without going into excitotoxic cell death themselves. It can be speculated that specific AMPA receptor inhibitors may protect normal neurons against the high glutamate microenvironment of GBM tumors.
多形性胶质母细胞瘤（GBM）细胞分泌大量谷氨酸，可触发AMPA型谷氨酸受体（AMPARs）。这通常会导致钠（Na⁺）和钙（Ca²⁺）通透性增加，进而导致周围神经元发生兴奋性毒性细胞死亡。在此，我们研究了GBM细胞自身如何在富含谷氨酸的环境中存活。
对已发表报告的计算机分析表明，与正常脑相比，GBM中所有离子型谷氨酸受体均下调。在体外，在所有测试的GBM样本中，与成人和胎儿全脑mRNA以及成人小脑mRNA相比，AMPAR亚基GluR1、2和4的mRNA表达相对较低。这些发现与原发性GBM样本一致，其中与正常组织相比，蛋白质表达模式下调。此外，还发现了这些受体的错误定位表达。对原发性和已建立的GBM细胞系中GluR2 RNA的序列分析表明，发现GluR2亚基部分未编辑。
结合NBQX对AMPAR抑制缺乏功能效应，我们的结果表明，AMPARs的下调和功能失调使GBM细胞能够在高谷氨酸环境中存活，而自身不会发生兴奋性毒性细胞死亡。可以推测，特定的AMPA受体抑制剂可能保护正常神经元免受GBM肿瘤高谷氨酸微环境的影响。
