IMP2-mediated regulation of OXPHOS promotes glioblastoma CSC survival and function.
Major finding: IMP2-mediated regulation of OXPHOS promotes glioblastoma CSC survival and function.
Mechanism: IMP2 enhances the assembly and activity of mitochondrial respiratory chain complex subunits.
Impact: CSCs expressing IMP2 may be more dependent on OXPHOS than on glycolysis for ATP production.
Although much is known about the role of cancer stem cells (CSC) in tumor initiation and therapeutic resistance, the energy requirements of CSCs are not well studied. Janiszewska and colleagues examined whether insulin-like growth factor 2 mRNA-binding protein 2 (IGF2BP2, also known as IMP2), which is expressed in the developing brain, is also functionally important in glioblastoma CSC energy production. IMP2 expression was elevated in human glioblastoma samples, particularly in cells positive for the glioblastoma CSC marker CD133, and in primary tumor gliomasphere cultures enriched for cells with CSC properties. Depletion of IMP2 in these CSC-like cells impaired sphere formation and cell viability, reduced the expression of stem cell factors, and suppressed tumorigenicity. Intriguingly, IMP2 was associated with factors known to regulate oxidative phosphorylation (OXPHOS), including mitochondrial respiratory chain complex I proteins and mRNAs encoding complex IV subunits, suggesting that IMP2 regulates mitochondrial metabolism and ATP generation in CSCs. Consistent with this idea, loss of IMP2 significantly decreased the rate of oxygen consumption, a measure of OXPHOS, and cellular ATP levels in gliomasphere CSC cultures. Similarly, inhibition of OXPHOS but not glycolysis abrogated sphere-derived CSC clonogenicity and oxygen consumption, whereas the proliferation and ATP levels of adherent glioblastoma cells were dependent on glycolysis. Furthermore, loss of IMP2 diminished the activity and assembly of complexes I and IV at the mitochondrial surface, suggesting that IMP2 may be required to deliver subunit-encoding mRNAs to the mitochondria for translation. Conversely, freshly isolated CD133-positive CSCs exhibited increased oxygen consumption, and overexpression of IMP2 in astrocytes enhanced mitochondrial activity. These findings identify a critical role for IMP2 in mitochondrial respiration and support the notion that glioblastoma CSCs may differ from more differentiated cancer cells in their reliance on OXPHOS for energy and survival.