title: Differential activity of NADPH-producing dehydrogenases renders rodents unsuitable models to study IDH1R132 mutation effects in human glioblastoma.
abstract: The somatic IDH1(R132) 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 IDH1(R132) mutation in glioblastoma.
authors.affiliation: Department of Cell Biology and Histology, Academic Medical Center, University of Amsterdam, Amsterdam, the Netherlands.
authors.forename: Nadia A
authors.initials: NA
authors.lastname: Atai
authors.forename: Nynke A
authors.initials: NA
authors.lastname: Renkema-Mills
authors.forename: Joost
authors.initials: J
authors.lastname: Bosman
authors.forename: Nadja
authors.initials: N
authors.lastname: Schmidt
authors.forename: Denise
authors.initials: D
authors.lastname: Rijkeboer
authors.forename: Wikky
authors.initials: W
authors.lastname: Tigchelaar
authors.forename: Klazien S
authors.initials: KS
authors.lastname: Bosch
authors.forename: Dirk
authors.initials: D
authors.lastname: Troost
authors.forename: Ard
authors.initials: A
authors.lastname: Jonker
authors.forename: Fonnet E
authors.initials: FE
authors.lastname: Bleeker
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Philip C
authors.initials: PC
authors.lastname: De Witt Hamer
authors.forename: Cornelis J F
authors.initials: CJ
authors.lastname: Van Noorden
mesh_terms: D000818:Animals; D001921:Brain / Q000201:enzymology; D001932:Brain Neoplasms / Q000201:enzymology* / Q000235:genetics; D005909:Glioblastoma / Q000201:enzymology* / Q000235:genetics; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D051379:Mice; D008810:Mice, Inbred C57BL; D023421:Models, Animal; D009154:Mutation; D009249:NADP / Q000096:biosynthesis*; D010088:Oxidoreductases / Q000096:biosynthesis*; D051381:Rats; D011923:Rats, Nude
chemical_list: D009249:NADP; D010088:Oxidoreductases; D007521:Isocitrate Dehydrogenase