title: D-2-Hydroxyglutarate does not mimic all the IDH mutation effects, in particular the reduced etoposide-triggered apoptosis mediated by an alteration in mitochondrial NADH.
abstract: Somatic mutations in isocitrate dehydrogenase (IDH)-1 and -2 have recently been described in glioma. This mutation leads to a neomorphic enzymatic activity as the conversion of isocitrate to alpha ketoglutarate (αKG) is replaced by the conversion of αKG to D-2-hydroxyglutarate (D-2HG) with NADPH oxidation. It has been suggested that this oncometabolite D-2HG via inhibition of αKG-dioxygenases is involved in multiple functions such as epigenetic modifications or hypoxia responses. The present study is aimed at deciphering how the mutant IDH can affect cancer pathogenesis, in particular with respect to its associated oncometabolite D-2HG. We show that the overexpression of mutant IDH in glioma cells or treatment with D-2HG triggered an increase in cell proliferation. However, although mutant IDH reduced cell sensitivity to the apoptotic inducer etoposide, D-2HG exhibited no effect on apoptosis. Instead, we found that the apoptotic effect was mediated through the mitochondrial NADH pool reduction and could be inhibited by oxamate. These data show that besides D-2HG production, mutant IDH affects other crucial metabolite pools. These observations lead to a better understanding of the biology of IDH mutations in gliomas and their response to therapy.
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France.
authors: K
authors: K
authors: Oizel
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France [3] Centre Hospitalier-Universitaire (CHU) de Nantes, Nantes F44093, France.
authors: C
authors: C
authors: Gratas
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France.
authors: A
authors: A
authors: Nadaradjane
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France [3] Centre Hospitalier-Universitaire (CHU) de Nantes, Nantes F44093, France.
authors: L
authors: L
authors: Oliver
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France [3] Institut de Cancérologie de l'Ouest - René Gauducheau, St Herblain F44805, France.
authors: F M
authors: FM
authors: Vallette
authors: 1] CRCNA - INSERM UMR 892 - CNRS UMR 6299, Nantes F44007, France [2] Faculté de Médecine, Université de Nantes, Nantes F44007, France.
authors: C
authors: C
authors: Pecqueur
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects / Q000235:genetics*; D005047:Etoposide / Q000008:administration & dosage; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D005910:Glioma / Q000235:genetics* / Q000473:pathology; D005977:Glutarates / Q000378:metabolism; D006801:Humans; D007521:Isocitrate Dehydrogenase / Q000096:biosynthesis / Q000235:genetics*; D007655:Ketoglutarate Dehydrogenase Complex; D008928:Mitochondria / Q000378:metabolism / Q000473:pathology; D009154:Mutation; D009243:NAD / Q000378:metabolism
chemical_list: D005977:Glutarates; D009243:NAD; C019417:alpha-hydroxyglutarate; D005047:Etoposide; C538784:IDH2 protein, human; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D007655:Ketoglutarate Dehydrogenase Complex