Autophagy and oxidative stress in gliomas with IDH1 mutations

Misty R. Gilbert, Yinxing Liu, Janna Neltner, H. Pu, Andrew Morris, Manjula Sunkara, Thomas Pittman, Natasha Kyprianou, Craig Horbinski

Research output: Contribution to journalArticle

29 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)221-233
Number of pages13
JournalActa Neuropathologica
Volume127
Issue number2
DOIs
Publication statusPublished - Feb 2014

Fingerprint

Autophagy
Glioma
Oxidative Stress
Mutation
Apoptosis
Superoxide Dismutase
Neoplasms
Heterografts
Survival
alpha-hydroxyglutarate

Keywords

  • Apoptosis
  • Autophagy
  • Glioma
  • IDH1
  • Oxidative stress

ASJC Scopus subject areas

  • Clinical Neurology
  • Pathology and Forensic Medicine
  • Cellular and Molecular Neuroscience

Cite this

Gilbert, M. R., Liu, Y., Neltner, J., Pu, H., Morris, A., Sunkara, M., ... Horbinski, C. (2014). Autophagy and oxidative stress in gliomas with IDH1 mutations. Acta Neuropathologica, 127(2), 221-233. https://doi.org/10.1007/s00401-013-1194-6

Autophagy and oxidative stress in gliomas with IDH1 mutations. / Gilbert, Misty R.; Liu, Yinxing; Neltner, Janna; Pu, H.; Morris, Andrew; Sunkara, Manjula; Pittman, Thomas; Kyprianou, Natasha; Horbinski, Craig.

In: Acta Neuropathologica, Vol. 127, No. 2, 02.2014, p. 221-233.

Research output: Contribution to journalArticle

Gilbert, MR, Liu, Y, Neltner, J, Pu, H, Morris, A, Sunkara, M, Pittman, T, Kyprianou, N & Horbinski, C 2014, 'Autophagy and oxidative stress in gliomas with IDH1 mutations', Acta Neuropathologica, vol. 127, no. 2, pp. 221-233. https://doi.org/10.1007/s00401-013-1194-6
Gilbert MR, Liu Y, Neltner J, Pu H, Morris A, Sunkara M et al. Autophagy and oxidative stress in gliomas with IDH1 mutations. Acta Neuropathologica. 2014 Feb;127(2):221-233. https://doi.org/10.1007/s00401-013-1194-6
Gilbert, Misty R. ; Liu, Yinxing ; Neltner, Janna ; Pu, H. ; Morris, Andrew ; Sunkara, Manjula ; Pittman, Thomas ; Kyprianou, Natasha ; Horbinski, Craig. / Autophagy and oxidative stress in gliomas with IDH1 mutations. In: Acta Neuropathologica. 2014 ; Vol. 127, No. 2. pp. 221-233.
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