title: The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration.
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.
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.|German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.
authors.forename: Georg
authors.initials: G
authors.lastname: Gdynia
authors.affiliation: Division of Inborn Metabolic Diseases, Department of General Pediatrics, University Children's Hospital, 69120 Heidelberg, Germany.
authors.forename: Sven W
authors.initials: SW
authors.lastname: Sauer
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Jürgen
authors.initials: J
authors.lastname: Kopitz
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Dominik
authors.initials: D
authors.lastname: Fuchs
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Katarina
authors.initials: K
authors.lastname: Duglova
authors.affiliation: Division of Inborn Metabolic Diseases, Department of General Pediatrics, University Children's Hospital, 69120 Heidelberg, Germany.
authors.forename: Thorsten
authors.initials: T
authors.lastname: Ruppert
authors.affiliation: German Cancer Research Center, Boveri Junior Research Group Innate Immunity, 69120 Heidelberg, Germany.
authors.forename: Matthias
authors.initials: M
authors.lastname: Miller
authors.affiliation: German Cancer Research Center, Boveri Junior Research Group Innate Immunity, 69120 Heidelberg, Germany.
authors.forename: Jens
authors.initials: J
authors.lastname: Pahl
authors.affiliation: German Cancer Research Center, Boveri Junior Research Group Innate Immunity, 69120 Heidelberg, Germany.
authors.forename: Adelheid
authors.initials: A
authors.lastname: Cerwenka
authors.affiliation: Institute of Inorganic Chemistry, Research Group Enders, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Enders
authors.affiliation: 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.
authors.forename: Heimo
authors.initials: H
authors.lastname: Mairbäurl
authors.affiliation: German Cancer Research Center, Division of Immunogenetics, Tumour Immunology Program, 69120 Heidelberg, Germany.
authors.forename: Marcin M
authors.initials: MM
authors.lastname: Kamiński
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
authors.forename: Roland
authors.initials: R
authors.lastname: Penzel
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.|German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.
authors.forename: Christine
authors.initials: C
authors.lastname: Zhang
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Department of Molecular and Cellular Modeling (MCM), 69118 Heidelberg, Germany.
authors.forename: Jonathan C
authors.initials: JC
authors.lastname: Fuller
authors.affiliation: Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Department of Molecular and Cellular Modeling (MCM), 69118 Heidelberg, Germany.|Center for Molecular Biology (ZMBH), Molecular and Cellular Modeling (MCM), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg 69120, Germany.|Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany.
authors.forename: Rebecca C
authors.initials: RC
authors.lastname: Wade
authors.affiliation: German Cancer Research Center, Division of Biostatistics, 69120 Heidelberg, Germany.
authors.forename: Axel
authors.initials: A
authors.lastname: Benner
authors.affiliation: Unit of Genetic Epidemiology, German Cancer Research Center, Division of Cancer Epidemiology, 69120 Heidelberg, Germany.|University Cancer Center Hamburg (UCCH), University Medical Center Hamburg- Eppendorf, 20246 Hamburg, Germany.
authors.forename: Jenny
authors.initials: J
authors.lastname: Chang-Claude
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.|German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Division of Preventive Oncology, 69120 Heidelberg, Germany.
authors.forename: Hermann
authors.initials: H
authors.lastname: Brenner
authors.affiliation: German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Hoffmeister
authors.affiliation: German Cancer Research Center, Division of Monoclonal Antibodies, 69120 Heidelberg, Germany.
authors.forename: Hanswalter
authors.initials: H
authors.lastname: Zentgraf
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.|German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.|Institute of Pathology, Department of Surgical Pathology, University Medical Center Mainz, University of Mainz, 55131 Mainz, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Schirmacher
authors.affiliation: Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.|German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.|Institute of Pathology, Department of Surgical Pathology, University Medical Center Mainz, University of Mainz, 55131 Mainz, Germany.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Roth
mesh_terms: D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D016923:Cell Death; D045744:Cell Line, Tumor; D019069:Cell Respiration; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics / Q000378:metabolism* / Q000503:physiopathology*; D005947:Glucose / Q000378:metabolism; D006019:Glycolysis; D024243:HMGB1 Protein / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism; D013963:Thyroid Hormones / Q000235:genetics / Q000378:metabolism; D000097810:Thyroid Hormone-Binding Proteins
chemical_list: D002352:Carrier Proteins; D005947:Glucose; D024243:HMGB1 Protein; D008565:Membrane Proteins; D013963:Thyroid Hormones; D000097810:Thyroid Hormone-Binding Proteins