OSMR controls glioma stem cell respiration and confers resistance of glioblastoma to ionizing radiation

Nat Commun. 2020 Aug 17;11(1):4116. doi: 10.1038/s41467-020-17885-z.


Glioblastoma contains a rare population of self-renewing brain tumor stem cells (BTSCs) which are endowed with properties to proliferate, spur the growth of new tumors, and at the same time, evade ionizing radiation (IR) and chemotherapy. However, the drivers of BTSC resistance to therapy remain unknown. The cytokine receptor for oncostatin M (OSMR) regulates BTSC proliferation and glioblastoma tumorigenesis. Here, we report our discovery of a mitochondrial OSMR that confers resistance to IR via regulation of oxidative phosphorylation, independent of its role in cell proliferation. Mechanistically, OSMR is targeted to the mitochondrial matrix via the presequence translocase-associated motor complex components, mtHSP70 and TIM44. OSMR interacts with NADH ubiquinone oxidoreductase 1/2 (NDUFS1/2) of complex I and promotes mitochondrial respiration. Deletion of OSMR impairs spare respiratory capacity, increases reactive oxygen species, and sensitizes BTSCs to IR-induced cell death. Importantly, suppression of OSMR improves glioblastoma response to IR and prolongs lifespan.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Death / radiation effects
  • Cell Line, Tumor
  • Cell Proliferation / radiation effects
  • Cell Survival / radiation effects
  • Cells, Cultured
  • Fluorescent Antibody Technique
  • Gene Expression Regulation, Neoplastic / radiation effects
  • Glioblastoma / metabolism*
  • Humans
  • Male
  • Mice
  • Mice, SCID
  • NADH Dehydrogenase / genetics
  • NADH Dehydrogenase / metabolism
  • Neoplastic Stem Cells / metabolism*
  • Neoplastic Stem Cells / radiation effects
  • Oncostatin M / metabolism
  • Oxidative Stress / radiation effects
  • Radiation, Ionizing*
  • Receptors, Oncostatin M / genetics
  • Receptors, Oncostatin M / metabolism*
  • STAT3 Transcription Factor / genetics
  • STAT3 Transcription Factor / metabolism
  • Signal Transduction / radiation effects


  • NDUFS1 protein, human
  • Receptors, Oncostatin M
  • STAT3 Transcription Factor
  • Oncostatin M
  • NADH Dehydrogenase
  • NDUFS2 protein, human