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The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration

Author

Listed:
  • Georg Gdynia

    (Institute of Pathology, University of Heidelberg
    German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology)

  • Sven W. Sauer

    (University Children’s Hospital)

  • Jürgen Kopitz

    (Institute of Pathology, University of Heidelberg)

  • Dominik Fuchs

    (Institute of Pathology, University of Heidelberg)

  • Katarina Duglova

    (Institute of Pathology, University of Heidelberg)

  • Thorsten Ruppert

    (University Children’s Hospital)

  • Matthias Miller

    (German Cancer Research Center, Boveri Junior Research Group Innate Immunity)

  • Jens Pahl

    (German Cancer Research Center, Boveri Junior Research Group Innate Immunity)

  • Adelheid Cerwenka

    (German Cancer Research Center, Boveri Junior Research Group Innate Immunity)

  • Markus Enders

    (Institute of Inorganic Chemistry, Research Group Enders, University of Heidelberg)

  • Heimo Mairbäurl

    (Medical Clinic VII, University of Heidelberg, and Translational Lung Research Center (TLRC), member of the German Center for Lung Research (DZL))

  • Marcin M. Kamiński

    (German Cancer Research Center, Tumour Immunology Program)

  • Roland Penzel

    (Institute of Pathology, University of Heidelberg)

  • Christine Zhang

    (Institute of Pathology, University of Heidelberg
    German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology)

  • Jonathan C. Fuller

    (Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS))

  • Rebecca C. Wade

    (Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS)
    Center for Molecular Biology (ZMBH), Molecular and Cellular Modeling (MCM), DKFZ-ZMBH Alliance, Heidelberg University
    Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University)

  • Axel Benner

    (German Cancer Research Center)

  • Jenny Chang-Claude

    (Unit of Genetic Epidemiology, German Cancer Research Center
    University Cancer Center Hamburg (UCCH), University Medical Center Hamburg- Eppendorf)

  • Hermann Brenner

    (German Cancer Research Center (DKFZ)
    German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT))

  • Michael Hoffmeister

    (German Cancer Research Center (DKFZ))

  • Hanswalter Zentgraf

    (German Cancer Research Center)

  • Peter Schirmacher

    (Institute of Pathology, University of Heidelberg
    German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology
    Institute of Pathology, University Medical Center Mainz, University of Mainz)

  • Wilfried Roth

    (Institute of Pathology, University of Heidelberg
    German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology
    Institute of Pathology, University Medical Center Mainz, University of Mainz)

Abstract

The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. Here we show that natural killer cell-derived HMGB1 directly eliminates cancer cells by triggering metabolic cell death. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, thus blocking glucose-driven aerobic respiration. This results in a rapid metabolic shift forcing cells to rely solely on glycolysis for the maintenance of energy production. Cancer cells can acquire resistance to HMGB1 by increasing glycolysis using the dimeric form of PKM2, and employing glutaminolysis. Consistently, we observe an increase in the expression of a key enzyme of glutaminolysis, malic enzyme 1, in advanced colon cancer. Moreover, pharmaceutical inhibition of glutaminolysis sensitizes tumour cells to HMGB1 providing a basis for a therapeutic strategy for treating cancer.

Suggested Citation

  • Georg Gdynia & Sven W. Sauer & Jürgen Kopitz & Dominik Fuchs & Katarina Duglova & Thorsten Ruppert & Matthias Miller & Jens Pahl & Adelheid Cerwenka & Markus Enders & Heimo Mairbäurl & Marcin M. Kamiń, 2016. "The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration," Nature Communications, Nature, vol. 7(1), pages 1-13, April.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms10764
    DOI: 10.1038/ncomms10764
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