title: Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells.
abstract: Fluctuations in oxygen tension during tissue remodeling impose a major metabolic challenge in human tumors. Stem-like tumor cells in glioblastoma, the most common malignant brain tumor, possess extraordinary metabolic flexibility, enabling them to initiate growth even under non-permissive conditions. We identified a reciprocal metabolic switch between the pentose phosphate pathway (PPP) and glycolysis in glioblastoma stem-like (GS) cells. Expression of PPP enzymes is upregulated by acute oxygenation but downregulated by hypoxia, whereas glycolysis enzymes, particularly those of the preparatory phase, are regulated inversely. Glucose flux through the PPP is reduced under hypoxia in favor of flux through glycolysis. PPP enzyme expression is elevated in human glioblastomas compared to normal brain, especially in highly proliferative tumor regions, whereas expression of parallel preparatory phase glycolysis enzymes is reduced in glioblastomas, except for strong upregulation in severely hypoxic regions. Hypoxia stimulates GS cell migration but reduces proliferation, whereas oxygenation has opposite effects, linking the metabolic switch to the "go or grow" potential of the cells. Our findings extend Warburg's observation that tumor cells predominantly utilize glycolysis for energy production, by suggesting that PPP activity is elevated in rapidly proliferating tumor cells but suppressed by acute severe hypoxic stress, favoring glycolysis and migration to protect cells against hypoxic cell damage.
authors.affiliation: Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany.
authors.forename: Annegret
authors.initials: A
authors.lastname: Kathagen
authors.forename: Alexander
authors.initials: A
authors.lastname: Schulte
authors.forename: Gerd
authors.initials: G
authors.lastname: Balcke
authors.forename: Heidi S
authors.initials: HS
authors.lastname: Phillips
authors.forename: Tobias
authors.initials: T
authors.lastname: Martens
authors.forename: Jakob
authors.initials: J
authors.lastname: Matschke
authors.forename: Hauke S
authors.initials: HS
authors.lastname: Günther
authors.forename: Robert
authors.initials: R
authors.lastname: Soriano
authors.forename: Zora
authors.initials: Z
authors.lastname: Modrusan
authors.forename: Thomas
authors.initials: T
authors.lastname: Sandmann
authors.forename: Carsten
authors.initials: C
authors.lastname: Kuhl
authors.forename: Alain
authors.initials: A
authors.lastname: Tissier
authors.forename: Mareike
authors.initials: M
authors.lastname: Holz
authors.forename: Lutz A
authors.initials: LA
authors.lastname: Krawinkel
authors.forename: Markus
authors.initials: M
authors.lastname: Glatzel
authors.forename: Manfred
authors.initials: M
authors.lastname: Westphal
authors.forename: Katrin
authors.initials: K
authors.lastname: Lamszus
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015687:Cell Hypoxia / Q000502:physiology; D049109:Cell Proliferation; D002478:Cells, Cultured; D005434:Flow Cytometry; D005910:Glioma / Q000378:metabolism*; D006019:Glycolysis / Q000502:physiology*; D064593:Heterografts; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D008819:Mice, Nude; D014411:Neoplastic Stem Cells / Q000378:metabolism*; D010100:Oxygen / Q000378:metabolism*; D010427:Pentose Phosphate Pathway / Q000502:physiology*; D060888:Real-Time Polymerase Chain Reaction; D059467:Transcriptome
chemical_list: D010100:Oxygen