title: Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment.
abstract: BACKGROUND
  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.
  
  
  RESULTS
  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.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Dannis G
authors.initials: DG
authors.lastname: van Vuurden
authors.forename: Maryam
authors.initials: M
authors.lastname: Yazdani
authors.forename: Ingeborg
authors.initials: I
authors.lastname: Bosma
authors.forename: Aart J F
authors.initials: AJ
authors.lastname: Broekhuizen
authors.forename: Tjeerd J
authors.initials: TJ
authors.lastname: Postma
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Heimans
authors.forename: Paul
authors.initials: P
authors.lastname: van der Valk
authors.forename: Eleonora
authors.initials: E
authors.lastname: Aronica
authors.forename: Bakhos A
authors.initials: BA
authors.lastname: Tannous
authors.forename: Thomas
authors.initials: T
authors.lastname: Würdinger
authors.forename: Gertjan J L
authors.initials: GJ
authors.lastname: Kaspers
authors.forename: Jacqueline
authors.initials: J
authors.lastname: Cloos
mesh_terms: D000818:Animals; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002118:Calcium / Q000737:chemistry; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D018698:Glutamic Acid / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry / Q000379:methods; D051379:Mice; D018091:Receptors, AMPA / Q000096:biosynthesis*; D012964:Sodium / Q000737:chemistry
chemical_list: D018091:Receptors, AMPA; D018698:Glutamic Acid; D012964:Sodium; D002118:Calcium