Lady Davis Institute for Medical Research, Jewish General Hospital, 3755 Chemin de la Côte-Sainte-Catherine, Montréal, QC, H3T 1E2, Canada.
Integrated program in Neuroscience, Montreal Neurological Institute, 3801 University Street, Montréal, QC, H3A 2B4, Canada.
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.
胶质母细胞瘤包含一小部分具有自我更新能力的脑肿瘤干细胞（BTSCs），它们具有增殖、促进新肿瘤生长的特性，同时还能逃避电离辐射（IR）和化疗。然而，BTSC 对治疗的耐药性的驱动因素尚不清楚。肿瘤坏死因子样细胞因子受体（OSMR）调节 BTSC 的增殖和胶质母细胞瘤的发生。在这里，我们报告了我们的发现，即一种线粒体 OSMR 通过调节氧化磷酸化赋予了对 IR 的抗性，这与其在细胞增殖中的作用无关。从机制上讲，OSMR 通过前导序列易位相关运动复合物成分 mtHSP70 和 TIM44 靶向线粒体基质。OSMR 与复合物 I 的 NADH 泛醌氧化还原酶 1/2（NDUFS1/2）相互作用并促进线粒体呼吸。OSMR 的缺失会损害备用呼吸能力，增加活性氧，并使 BTSC 对 IR 诱导的细胞死亡敏感。重要的是，抑制 OSMR 可提高胶质母细胞瘤对 IR 的反应并延长生存期。
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