Abstract
BackgroundGlioblastoma multiforme (GBM) cells secrete large amounts of glutamate that can trigger AMPA-type glutamate receptors (AMPARs). This commonly results in Na+ and Ca2+-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.Methods and Findings 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.ConclusionsTogether 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.
Highlights
High-grade gliomas (glioblastoma multiforme (GBM)) are the most common aggressive malignant brain tumors
Together with the lack of functional effect of AMPA-type glutamate receptors (AMPARs) inhibition by NBQX our results suggest that downregulation and afunctionality of AMPARs, enable Glioblastoma multiforme (GBM) cells to survive in a high glutamate environment without going into excitotoxic cell death themselves
AMPA receptor blockage with NBQX (2,3-dihydroxy-6-nitro-7-sulfamoyl-benzo[f]quinoxaline-2,3-dione), a potent competitive AMPA receptor antagonist, conveyed no effect on cell proliferation. These results suggest that down-regulation of functional AMPAR expression is a mechanism allowing GBM cells to escape excitotoxic cell death
Summary
High-grade gliomas (glioblastoma multiforme (GBM)) are the most common aggressive malignant brain tumors. One of the major neurotransmitters in the central nervous system, and its metabolism via receptors and transporters, is thought to be a contributing factor to the malignant behavior of GBM [4,5]. Glutamate binds to both ligand gated ion channels - NMDA (N-methyl-D-apertate), AMPA (a-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid), kainate receptors - and metabotropic glutamate receptors [6]. Glioblastoma multiforme (GBM) cells secrete large amounts of glutamate that can trigger AMPA-type glutamate receptors (AMPARs) This commonly results in Na+ and Ca2+-permeability and thereby in excitotoxic cell death of the surrounding neurons. We investigated how the GBM cells themselves survive in a glutamate-rich environment
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