Imp2 controls oxidative phosphorylation and is crucial for preserving glioblastoma cancer stem cells

Genes and Development - Tập 26 Số 17 - Trang 1926-1944 - 2012
Michalina Janiszewska1, Mario L. Suvà2, Nicolò Riggi2, Riekelt H. Houtkooper3,4, Johan Auwerx3, Virginie Clément‐Schatlo5, Ivan Radovanovic5, Esther Rheinbay2,6, Paolo Provero7, Ivan Stamenkovic1
11Experimental Pathology, Department of Laboratories, CHUV, University of Lausanne, Lausanne CH-1011, Switzerland;
22James Homer Wright Pathology Laboratories, Department of Pathology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA;
33Laboratory for Integrative and Systems Physiology, Nestle Chair in Energy Metabolism (NCEM), Ecole Polytechnique Fédérale de Lausanne, Lausanne CH-1015, Switzerland;
44Laboratory Genetic Metabolic Diseases, University of Amsterdam, Academic Medical Center, Amsterdam 1105 AZ, Netherlands;
55Department of Clinical Neurosciences, University Hospital of Geneva, Geneva CH-1211, Switzerland;
66Bioinformatics Program, Boston University, Boston, Massachusetts 02215, USA;
77Department of Genetics, Biology, and Biochemistry, University of Torino, Torino 10126 Italy

Tóm tắt

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.

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Genes and Development

Tập 26 Số 17

1926-1944

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