title: IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo.
abstract: OBJECTIVE
  A high percentage of grade II and III gliomas have mutations in the gene encoding isocitrate dehydrogenase (IDH1). This mutation is always a heterozygous point mutation that affects the amino acid arginine at position 132 and results in loss of its native enzymatic activity and gain of alternative enzymatic activity (producing D-2-hydroxyglutarate). The objective of this study was to investigate the cellular effects of R132H mutations in IDH1.
  
  
  METHODS
  Functional consequences of IDH1(R132H) mutations were examined among others using fluorescence-activated cell sorting, kinome and expression arrays, biochemical assays, and intracranial injections on 3 different (glioma) cell lines with stable overexpression of IDH1(R132H) .
  
  
  RESULTS
  IDH1(R132H) overexpression in established glioma cell lines in vitro resulted in a marked decrease in proliferation, decreased Akt phosphorylation, altered morphology, and a more contact-dependent cell migration. The reduced proliferation is related to accumulation of D-2-hydroxyglutarate that is produced by IDH1(R132H) . Mice injected with IDH1(R132H) U87 cells have prolonged survival compared to mice injected with IDH1(wt) or green fluorescent protein-expressing U87 cells.
  
  
  CONCLUSIONS
  Our results demonstrate that IDH1(R132H) dominantly reduces aggressiveness of established glioma cell lines in vitro and in vivo. In addition, the IDH1(R132H) -IDH1(wt) heterodimer has higher enzymatic activity than the IDH1(R132H) -IDH1(R132H) homodimer. Our observations in model systems of glioma might lead to a better understanding of the biology of IDH1 mutant gliomas, which are typically low grade and often slow growing.
authors: Department of Neurology, Erasmus Medical Center, Rotterdam, the Netherlands.
authors: Linda B C
authors: LB
authors: Bralten
authors: Nanne K
authors: NK
authors: Kloosterhof
authors: Rutger
authors: R
authors: Balvers
authors: Andrea
authors: A
authors: Sacchetti
authors: Lariesa
authors: L
authors: Lapre
authors: Martine
authors: M
authors: Lamfers
authors: Sieger
authors: S
authors: Leenstra
authors: Hugo
authors: H
authors: de Jonge
authors: Johan M
authors: JM
authors: Kros
authors: Erwin E W
authors: EE
authors: Jansen
authors: Eduard A
authors: EA
authors: Struys
authors: Cornelis
authors: C
authors: Jakobs
authors: Gajja S
authors: GS
authors: Salomons
authors: Sander H
authors: SH
authors: Diks
authors: Maikel
authors: M
authors: Peppelenbosch
authors: Andreas
authors: A
authors: Kremer
authors: Casper C
authors: CC
authors: Hoogenraad
authors: Peter A E Sillevis
authors: PA
authors: Smitt
authors: Pim J
authors: PJ
authors: French
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D010766:Phosphorylation / Q000235:genetics; D017354:Point Mutation / Q000235:genetics*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D015398:Signal Transduction / Q000235:genetics
chemical_list: D007521:Isocitrate Dehydrogenase; D051057:Proto-Oncogene Proteins c-akt