Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells.
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.
Experimental Pathology, Department of Laboratories, CHUV, University of Lausanne, Lausanne CH-1011, Switzerland.
Michalina
M
Janiszewska
Mario L
ML
Suvà
Nicolo
N
Riggi
Riekelt H
RH
Houtkooper
Johan
J
Auwerx
Virginie
V
Clément-Schatlo
Ivan
I
Radovanovic
Esther
E
Rheinbay
Paolo
P
Provero
Ivan
I
Stamenkovic
D000818:Animals; D001921:Brain / Q000378:metabolism; D015687:Cell Hypoxia / Q000502:physiology; D002460:Cell Line; D005786:Gene Expression Regulation; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D008928:Mitochondria / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010085:Oxidative Phosphorylation / Q000187:drug effects; D011485:Protein Binding; D012333:RNA, Messenger / Q000378:metabolism; D034741:RNA, Small Interfering / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D012402:Rotenone / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D014475:Uncoupling Agents / Q000494:pharmacology
C498779:IGF2BP2 protein, human; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D016601:RNA-Binding Proteins; D014475:Uncoupling Agents; D012402:Rotenone