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


Ontology type: schema:ScholarlyArticle      Open Access: True


Article Info

DATE

2016-03-07

AUTHORS

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. Kamiński, Roland Penzel, Christine Zhang, Jonathan C. Fuller, Rebecca C. Wade, Axel Benner, Jenny Chang-Claude, Hermann Brenner, Michael Hoffmeister, Hanswalter Zentgraf, Peter Schirmacher, Wilfried Roth

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. More... »

PAGES

10764

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  • Identifiers

    URI

    http://scigraph.springernature.com/pub.10.1038/ncomms10764

    DOI

    http://dx.doi.org/10.1038/ncomms10764

    DIMENSIONS

    https://app.dimensions.ai/details/publication/pub.1040719607

    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/26948869


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    436 German Cancer Research Center, Division of Monoclonal Antibodies, 69120 Heidelberg, Germany
    437 Institute of Pathology, Department of Surgical Pathology, University Medical Center Mainz, University of Mainz, 55131 Mainz, Germany
    438 Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany
    439 rdf:type schema:Organization
    440 https://www.grid.ac/institutes/grid.7700.0 schema:alternateName Heidelberg University
    441 schema:name Center for Molecular Biology (ZMBH), Molecular and Cellular Modeling (MCM), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg 69120, Germany
    442 Institute of Inorganic Chemistry, Research Group Enders, University of Heidelberg, 69120 Heidelberg, Germany
    443 Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany
    444 Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany
    445 Medical Clinic VII, Department of Sports Medicine, University of Heidelberg, and Translational Lung Research Center (TLRC), member of the German Center for Lung Research (DZL), 69120 Heidelberg, Germany
    446 Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Department of Molecular and Cellular Modeling (MCM), 69118 Heidelberg, Germany
    447 rdf:type schema:Organization
     




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