Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells
Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells
复制标题
DOI：
10.1101/gad.188292.112
复制
发表时间：
2012-09-01
影响因子：
10.5
通讯作者：
Stamenkovic, Ivan
中科院分区：
文献类型：
--
作者：
Janiszewska, Michalina;Suva, Mario L.;Stamenkovic, Ivan
许多癌症类型的生长被认为是由低分化细胞的亚群驱动的，通常被称为癌症干细胞（CSC），其具有自我更新、肿瘤起始和产生非致瘤性后代的能力。尽管它们在肿瘤的建立和维持中具有潜在的关键作用，但这些细胞的能量需求以及调节其能量产生的机制尚不清楚。在这里，我们表明，癌胚胰岛素样生长因子2 mRNA结合蛋白2（IMP2，IGF2BP2）调节氧化磷酸化（OXPHOS）在原发性胶质母细胞瘤（GBM）球文化（gliomaspheres），一个既定的体外模型CSC的扩张。我们证明，IMP2结合几种编码线粒体呼吸链复合物亚基的mRNA，并与复合物I（NADH：泛醌氧化还原酶）蛋白相互作用。神经胶质球中IMP 2的消耗降低了它们的耗氧速率以及复合物I和复合物IV的活性，这导致体外克隆形成性和体内致瘤性受损。重要的是，抑制OXPHOS而不是糖酵解消除GBM细胞集落形成。我们的观察结果表明，神经胶质球依赖于OXPHOS的能量产生和生存，IMP 2的表达提供了一个关键的机制，以确保OXPHOS的维护，通过提供呼吸链亚基编码的mRNA的线粒体，并有助于复合物I和复合物IV组装。
Growth of numerous cancer types is believed to be driven by a subpopulation of poorly differentiated cells, often referred to as cancer stem cells (CSCs), that have the capacity for self-renewal, tumor initiation, and generation of nontumorigenic progeny. Despite their potentially key role in tumor establishment and maintenance, the energy requirements of these cells and the mechanisms that regulate their energy production are unknown. Here, we show that the oncofetal insulin-like growth factor 2 mRNA-binding protein 2 (IMP2, IGF2BP2) regulates oxidative phosphorylation (OXPHOS) in primary glioblastoma (GBM) sphere cultures (gliomaspheres), an established in vitro model for CSC expansion. We demonstrate that IMP2 binds several mRNAs that encode mitochondrial respiratory chain complex subunits and that it interacts with complex I (NADH: ubiquinone oxidoreductase) proteins. Depletion of IMP2 in gliomaspheres decreases their oxygen consumption rate and both complex I and complex IV activity that results in impaired clonogenicity in vitro and tumorigenicity in vivo. Importantly, inhibition of OXPHOS but not of glycolysis abolishes GBM cell clonogenicity. Our observations suggest that gliomaspheres depend on OXPHOS for their energy production and survival and that IMP2 expression provides a key mechanism to ensure OXPHOS maintenance by delivering respiratory chain subunit-encoding mRNAs to mitochondria and contributing to complex I and complex IV assembly.