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Nat Commun. 2016 Mar 7;7:10764. doi: 10.1038/ncomms10764.

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

Author information

1
Institute of Pathology, Department of Surgical Pathology, University of Heidelberg, 69120 Heidelberg, Germany.
2
German Cancer Research Center, Clinical Cooperation Unit Molecular Tumor Pathology, 69120 Heidelberg, Germany.
3
Division of Inborn Metabolic Diseases, Department of General Pediatrics, University Children's Hospital, 69120 Heidelberg, Germany.
4
German Cancer Research Center, Boveri Junior Research Group Innate Immunity, 69120 Heidelberg, Germany.
5
Institute of Inorganic Chemistry, Research Group Enders, University of Heidelberg, 69120 Heidelberg, Germany.
6
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.
7
German Cancer Research Center, Division of Immunogenetics, Tumour Immunology Program, 69120 Heidelberg, Germany.
8
Molecular and Cellular Modeling Group, Heidelberg Institute for Theoretical Studies (HITS), Department of Molecular and Cellular Modeling (MCM), 69118 Heidelberg, Germany.
9
Center for Molecular Biology (ZMBH), Molecular and Cellular Modeling (MCM), DKFZ-ZMBH Alliance, Heidelberg University, Heidelberg 69120, Germany.
10
Interdisciplinary Center for Scientific Computing (IWR), Heidelberg University, 69120 Heidelberg, Germany.
11
German Cancer Research Center, Division of Biostatistics, 69120 Heidelberg, Germany.
12
Unit of Genetic Epidemiology, German Cancer Research Center, Division of Cancer Epidemiology, 69120 Heidelberg, Germany.
13
University Cancer Center Hamburg (UCCH), University Medical Center Hamburg- Eppendorf, 20246 Hamburg, Germany.
14
German Cancer Research Center (DKFZ), Division of Clinical Epidemiology and Aging Research, 69120 Heidelberg, Germany.
15
German Cancer Research Center (DKFZ) and National Center for Tumor Diseases (NCT), Division of Preventive Oncology, 69120 Heidelberg, Germany.
16
German Cancer Research Center, Division of Monoclonal Antibodies, 69120 Heidelberg, Germany.
17
Institute of Pathology, Department of Surgical Pathology, University Medical Center Mainz, University of Mainz, 55131 Mainz, Germany.

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.

PMID:
26948869
PMCID:
PMC4786644
DOI:
10.1038/ncomms10764
[Indexed for MEDLINE]
Free PMC Article

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