Differential Activity of NADPH-Producing Dehydrogenases Renders Rodents Unsuitable Models to Study IDH1^R132 Mutation Effects in Human Glioblastoma

Abstract

The somatic IDH1R132 mutation in the isocitrate dehydrogenase 1 gene occurs in high frequency in glioma and in lower frequency in acute myeloid leukemia and thyroid cancer but not in other types of cancer. The mutation causes reduced NADPH production capacity in glioblastoma by 40% and is associated with prolonged patient survival. NADPH is a major reducing compound in cells that is essential for detoxification and may be involved in resistance of glioblastoma to treatment. IDH has never been considered important in NADPH production. Therefore, the authors investigated NADPH-producing dehydrogenases using in silico analysis of human cancer gene expression microarray data sets and metabolic mapping of human and rodent tissues to determine the role of IDH in total NADPH production. Expression of most NADPH-producing dehydrogenase genes was not elevated in 34 cancer data sets except for IDH1 in glioma and thyroid cancer, indicating an association with the IDH1 mutation. IDH activity was the main provider of NADPH in human normal brain and glioblastoma, but its role was modest in NADPH production in rodent brain and other tissues. It is concluded that rodents are a poor model to study consequences of the IDH1R132 mutation in glioblastoma.

IDH1andIDH2Mutations in Tumorigenesis: Mechanistic Insights and Clinical Perspectives

“…As reducing oxidative stress and increasing fatty acid synthesis are required for cell division, NADPH is an important metabolite for the proliferation of both normal and tumor cells. IDH1 mutation was previously found to result in lowered NADPH tissue levels (58), although no difference in NADPH levels was observed in another study (59). Whether reduced NAPDH production by the mutations targeting IDH1/2 causes decreased cell proliferation, thus contributing to relatively slower tumor growth, or is being compensated by the increased activity of other NADPH producing enzymes has not been determined.…”

The Potential for Isocitrate Dehydrogenase Mutations to Produce 2-Hydroxyglutarate Depends on Allele Specificity and Subcellular Compartmentalization

“…Further studies in non-transformed cell lines will be needed to test the dependence of 2HG production from cytosolic mutant IDH1 on the prior induction of growth factor signaling and increased wild-type IDH1 activity. But this hypothesis may partially explain the failure (to date) of genetically engineered mouse models to demonstrate the initiation of tumorigenesis by IDH1 mutation in a stem/progenitor cell (34,41,42). It appears from the present data that 2HG production from cytosolic mutant IDH1 is a dynamic process that is acutely sensitive to the background metabolic state of the cell.…”

Glioma diagnostics and biomarkers: an ongoing challenge in the field of medicine and science

“…GBM, the most aggressive, is characterized by cells with nuclear atypia and high mitotic rates with contiguous areas of new vessel formation and necrosis. The incidence of GBM is about 3.5 per 100.000 people per year with a mean overall survival of 1.5 years [1]. Patients with a less aggressive glioma have longer survival with concomitant morbidity but cure is uncommon.…”