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

• Published in: Nature communications Vol. 11; no. 1; pp. 4116 - 16
• Main Authors: Sharanek, Ahmad, Burban, Audrey, Laaper, Matthew, Heckel, Emilie, Joyal, Jean-Sebastien, Soleimani, Vahab D., Jahani-Asl, Arezu
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 17.08.2020; Nature Publishing Group; Nature Portfolio
• Subjects: 13/100; 14/19; 631/67/1922; 631/67/2327; 631/67/71; 64/60; 82/80; 96/31; Brain cancer; Brain stem; Brain tumors; Cancer; Cell death; Cell growth; Cell proliferation; Chemotherapy; Cytokines; Electron transport chain; Glioblastoma; Glioma; Glioma cells; Humanities and Social Sciences; Impact resistance; Ionizing radiation; Life Sciences; Life span; Mitochondria; multidisciplinary; NADH; Nicotinamide adenine dinucleotide; Oncostatin M; Oxidation resistance; Oxidative phosphorylation; Phosphorylation; Radiation tolerance; Reactive oxygen species; Receptors; Respiration; Science; Science (multidisciplinary); Stem cells; Translocase; Tumorigenesis; Tumors; Ubiquinone; Ubiquinone oxidoreductase
• ISSN: 2041-1723; 2041-1723
• 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. The suppression of the receptor for oncostatin M (OSMR) can prevent glioblastoma cell growth. Here, the authors demonstrate a role for OSMR in modulating glioma stem cell respiration and its impact on resistance to ionizing radiation.