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

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 and Wilfried Roth
Additional contact information
Georg Gdynia: Institute of Pathology, University of Heidelberg
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
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)
Axel Benner: German Cancer Research Center
Jenny Chang-Claude: Unit of Genetic Epidemiology, German Cancer Research Center
Hermann Brenner: German Cancer Research Center (DKFZ)
Michael Hoffmeister: German Cancer Research Center (DKFZ)
Hanswalter Zentgraf: German Cancer Research Center
Peter Schirmacher: Institute of Pathology, University of Heidelberg
Wilfried Roth: Institute of Pathology, University of Heidelberg

Nature Communications, 2016, vol. 7, issue 1, 1-13

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms10764

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