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

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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.

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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.

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Authors and Affiliations

  1. Laboratory for Brain Tumor Biology, Department of Neurosurgery, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246, Hamburg, Germany

    Annegret Kathagen, Alexander Schulte, Tobias Martens, Hauke S. Günther, Mareike Holz, Lutz A. Krawinkel, Manfred Westphal & Katrin Lamszus

  2. Department of Cell and Metabolic Biology, Leibniz Institute of Plant Biochemistry, Halle, Germany

    Gerd Balcke & Alain Tissier

  3. Department of Translational Oncology, Genentech, Inc., South San Francisco, CA, USA

    Heidi S. Phillips

  4. Institute of Neuropathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

    Jakob Matschke & Markus Glatzel

  5. Department of Molecular Biology, Genentech, Inc., South San Francisco, CA, USA

    Robert Soriano & Zora Modrusan

  6. Department of Bioinformatics and Computational Biology, Genentech, Inc., South San Francisco, CA, USA

    Thomas Sandmann

  7. Department of Stress and Developmental Biology, Leibniz Institute of Plant Biochemistry, Halle, Germany

    Carsten Kuhl

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  1. Annegret Kathagen
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Correspondence to Katrin Lamszus.

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Kathagen, A., Schulte, A., Balcke, G. et al. Hypoxia and oxygenation induce a metabolic switch between pentose phosphate pathway and glycolysis in glioma stem-like cells. Acta Neuropathol 126, 763–780 (2013). https://doi.org/10.1007/s00401-013-1173-y

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