IDH1 R132H decreases proliferation of glioma cell lines in vitro and in vivo

作者：Linda B.C. Bralten, Nanne K. Kloosterhof, Rutger K. Balvers, Andrea Sacchetti, Lariesa Lapre, Martine L.M. Lamfers, Sieger Leenstra, Hugo de Jonge, Johan M. Kros, Erwin E. W. Jansen, Eduard A. Struys, Cornelis Jakobs, Gajja Sophi Salomons, Sander H. Diks, Maikel Petrus Peppelenbosch, Andreas Kremer, Casper C. Hoogenraad, Peter A.E. Sillevis Smitt, Pim J. French · 发表于：Annals of Neurology · 年份：2011 · DOI：10.1002/ana.22390 · 被引用次数：141 · 研究领域：Glioma Diagnosis and Treatment、Amino Acid Enzymes and Metabolism、Cancer Research and Treatments

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. INTERPRETATION: 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) homodi...