title: Autophagy and oxidative stress in gliomas with IDH1 mutations.
abstract: IDH1 mutations in gliomas associate with longer survival. Prooxidant and antiproliferative effects of IDH1 mutations and its D-2-hydroxyglutarate (2-HG) product have been described in vitro, but inconsistently observed. It is also unclear whether overexpression of mutant IDH1 in wild-type cells accurately phenocopies the effects of endogenous IDH1-mutations on tumor apoptosis and autophagy. Herein we investigated the effects of 2-HG and mutant IDH1 overexpression on proliferation, apoptosis, oxidative stress, and autophagy in IDH1 wild-type glioma cells, and compared those results with patient-derived tumors. 2-HG reduced viability and proliferation of U87MG and LN18 cells, triggered apoptosis in LN18 cells, and autophagy in U87MG cells. In vitro studies and flank xenografts of U87MG cells overexpressing R132H IDH1 exhibited increased oxidative stress, including increases of both manganese superoxide dismutase (MnSOD) and p62. Patient-derived IDH1-mutant tumors showed no significant differences in apoptosis or autophagy, but showed p62 accumulation and actually trended toward reduced MnSOD expression. These data indicate that mutant IDH1 and 2-HG can induce oxidative stress, autophagy, and apoptosis, but these effects vary greatly according to cell type.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Kentucky, 307 Combs Building, Lexington, KY, 40536, USA.
authors.forename: Misty R
authors.initials: MR
authors.lastname: Gilbert
authors.forename: Yinxing
authors.initials: Y
authors.lastname: Liu
authors.forename: Janna
authors.initials: J
authors.lastname: Neltner
authors.forename: Hong
authors.initials: H
authors.lastname: Pu
authors.forename: Andrew
authors.initials: A
authors.lastname: Morris
authors.forename: Manjula
authors.initials: M
authors.lastname: Sunkara
authors.forename: Thomas
authors.initials: T
authors.lastname: Pittman
authors.forename: Natasha
authors.initials: N
authors.lastname: Kyprianou
authors.forename: Craig
authors.initials: C
authors.lastname: Horbinski
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001343:Autophagy / Q000502:physiology*; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016543:Central Nervous System Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005260:Female; D005910:Glioma / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology*; D005977:Glutarates / Q000378:metabolism; D064593:Heterografts; D006801:Humans; D066298:In Vitro Techniques; D007521:Isocitrate Dehydrogenase / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D009154:Mutation / Q000235:genetics*; D018384:Oxidative Stress / Q000502:physiology*; D000071456:Sequestosome-1 Protein; D013482:Superoxide Dismutase / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D005977:Glutarates; C099718:SQSTM1 protein, human; D000071456:Sequestosome-1 Protein; C019417:alpha-hydroxyglutarate; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D013482:Superoxide Dismutase; D020169:Caspases