Attenuated AMPA receptor expression allows glioblastoma cell survival in glutamate-rich environment.
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.
van Vuurden
Dannis G
DG
Department of Pediatric Oncology/Hematology, VU University Medical Center, Amsterdam, The Netherlands.
Yazdani
Maryam
M
Bosma
Ingeborg
I
Broekhuizen
Aart J F
AJ
Postma
Tjeerd J
TJ
Heimans
Jan J
JJ
van der Valk
Paul
P
Aronica
Eleonora
E
Tannous
Bakhos A
BA
Würdinger
Thomas
T
Kaspers
Gertjan J L
GJ
Cloos
Jacqueline
J
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
D018091:Receptors, AMPA; D018698:Glutamic Acid; D012964:Sodium; D002118:Calcium