title: Evidence for transcriptional regulation of the glucose-6-phosphate transporter by HIF-1alpha: Targeting G6PT with mumbaistatin analogs in hypoxic mesenchymal stromal cells.
abstract: 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.
authors.affiliation: Département de Chimie, Centre BIOMED, Université du Québec à Montréal, Canada.
authors.forename: Simon
authors.initials: S
authors.lastname: Lord-Dufour
authors.forename: Ian B
authors.initials: IB
authors.lastname: Copland
authors.forename: Louis-Charles
authors.initials: LC
authors.lastname: Levros
authors.forename: Martin
authors.initials: M
authors.lastname: Post
authors.forename: Abhirup
authors.initials: A
authors.lastname: Das
authors.forename: Chaitan
authors.initials: C
authors.lastname: Khosla
authors.forename: Jacques
authors.initials: J
authors.lastname: Galipeau
authors.forename: Eric
authors.initials: E
authors.lastname: Rassart
authors.forename: Borhane
authors.initials: B
authors.lastname: Annabi
mesh_terms: D000818:Animals; D000880:Anthraquinones / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D015687:Cell Hypoxia / Q000187:drug effects; D002465:Cell Movement; D002478:Cells, Cultured; D003035:Cobalt / Q000494:pharmacology; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D015870:Gene Expression / Q000187:drug effects*; D005952:Glucose-6-Phosphatase / Q000235:genetics; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics / Q000502:physiology*; D015151:Immunoblotting; D059630:Mesenchymal Stem Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009004:Monosaccharide Transport Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000502:physiology*; D009336:Necrosis / Q000235:genetics; D034622:RNA Interference; D020133:Reverse Transcriptase Polymerase Chain Reaction; D017154:Stromal Cells / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*
chemical_list: D000880:Anthraquinones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009004:Monosaccharide Transport Proteins; C430985:mumbaistatin; D003035:Cobalt; D005952:Glucose-6-Phosphatase; C018021:cobaltous chloride