Mesenchymal stromal cell (MSC) markers are expressed on
brain tumor-initiating cells involved in the development of hypoxic
glioblastoma. Given that MSCs can survive
hypoxia and that the
glucose-6-phosphate transporter (G6PT) provides metabolic control that contributes to MSC mobilization and survival, we investigated the effects of low
oxygen (1.2% O(2)) exposure on G6PT gene expression. We found that MSCs significantly expressed G6PT and the
glucose-6-phosphatase catalytic subunit beta, whereas expression of the
glucose-6-phosphatase catalytic subunit alpha and the islet-specific
glucose-6-phosphatase catalytic subunit-related
protein was low to undetectable. Analysis of the G6PT promoter sequence revealed potential binding sites for
hypoxia inducible factor (HIF)-1alpha and for the
aryl hydrocarbon receptor (AhR) and its dimerization partner, the
AhR nuclear translocator (ARNT), AhR:ARNT. In agreement with this,
hypoxia and the
hypoxia mimetic
cobalt chloride induced the expression of G6PT,
vascular endothelial growth factor (
VEGF), and HIF-1alpha. Gene silencing of HIF-1alpha prevented G6PT and
VEGF induction in hypoxic MSCs whereas generation of cells stably expressing HIF-1alpha resulted in increased endogenous G6PT gene expression. A semisynthetic analog of the
polyketide mumbaistatin, a potent G6PT inhibitor, specifically reduced MSC-HIF-1alpha cell survival. Collectively, our data suggest that G6PT may account for the metabolic flexibility that enables MSCs to survive under conditions characterized by
hypoxia and could be specifically targeted within developing
tumors.