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Acta Neuropathologica

, Volume 126, Issue 5, pp 763–780 | Cite as

Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells

  • Annegret Kathagen
  • Alexander Schulte
  • Gerd Balcke
  • Heidi S. Phillips
  • Tobias Martens
  • Jakob Matschke
  • Hauke S. Günther
  • Robert Soriano
  • Zora Modrusan
  • Thomas Sandmann
  • Carsten Kuhl
  • Alain Tissier
  • Mareike Holz
  • Lutz A. Krawinkel
  • Markus Glatzel
  • Manfred Westphal
  • Katrin LamszusEmail author
Original Paper

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.

Keywords

Glioblastoma stem cells Hypoxia Glycolysis Pentose phosphate pathway Migration Invasion 

Notes

Acknowledgments

We thank Anna Schöttler, Svenja Zapf, Hildegard Meissner and Regina Peters for expert technical assistance. Annegret Kathagen is a scholar of the Konrad-Adenauer-Stiftung. This work was supported by the Deutsche Forschungsgemeinschaft (LA1300/4-1), Deutsche Krebshilfe, Georg and Jürgen Rickertsen Stiftung and the Rudolf Bartling Stiftung. We further thank the UKE FACS Core Facility for their support on flow cytometric analyses.

Supplementary material

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Supplementary material 5 (DOC 57 kb)
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Supplementary material 6 (DOC 60 kb)

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Copyright information

© Springer-Verlag Berlin Heidelberg 2013

Authors and Affiliations

  • Annegret Kathagen
    • 1
  • Alexander Schulte
    • 1
  • Gerd Balcke
    • 2
  • Heidi S. Phillips
    • 3
  • Tobias Martens
    • 1
  • Jakob Matschke
    • 4
  • Hauke S. Günther
    • 1
  • Robert Soriano
    • 5
  • Zora Modrusan
    • 5
  • Thomas Sandmann
    • 6
  • Carsten Kuhl
    • 7
  • Alain Tissier
    • 2
  • Mareike Holz
    • 1
  • Lutz A. Krawinkel
    • 1
  • Markus Glatzel
    • 4
  • Manfred Westphal
    • 1
  • Katrin Lamszus
    • 1
    Email author
  1. 1.Laboratory for Brain Tumor Biology, Department of NeurosurgeryUniversity Medical Center Hamburg-EppendorfHamburgGermany
  2. 2.Department of Cell and Metabolic BiologyLeibniz Institute of Plant BiochemistryHalleGermany
  3. 3.Department of Translational OncologyGenentech, Inc.South San FranciscoUSA
  4. 4.Institute of NeuropathologyUniversity Medical Center Hamburg-EppendorfHamburgGermany
  5. 5.Department of Molecular BiologyGenentech, Inc.South San FranciscoUSA
  6. 6.Department of Bioinformatics and Computational BiologyGenentech, Inc.South San FranciscoUSA
  7. 7.Department of Stress and Developmental BiologyLeibniz Institute of Plant BiochemistryHalleGermany

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