The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration
| Autor: | Peter Schirmacher, Thorsten Ruppert, Jens Pahl, Axel Benner, Jonathan C. Fuller, Katarina Duglova, Jenny Chang-Claude, Roland Penzel, Adelheid Cerwenka, Hanswalter Zentgraf, Hermann Brenner, Heimo Mairbäurl, Michael Hoffmeister, Georg Gdynia, Marcin Kamiński, Wilfried Roth, Dominik Fuchs, Markus Enders, Rebecca C. Wade, Sven W. Sauer, Jürgen Kopitz, Matthias Miller, Christine Zhang |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Programmed cell death Thyroid Hormones Cellular respiration Science Cell Respiration Malic enzyme General Physics and Astronomy chemical and pharmacologic phenomena PKM2 Biology General Biochemistry Genetics and Molecular Biology Article 03 medical and health sciences Cell Line Tumor Humans Glycolysis HMGB1 Protein Multidisciplinary Glutaminolysis Cell Death Membrane Proteins General Chemistry Cell biology 030104 developmental biology Glucose Cancer cell Colonic Neoplasms Carrier Proteins Pyruvate kinase |
| Zdroj: | Nature Communications Nature Communications, Vol 7, Iss 1, Pp 1-13 (2016) |
| ISSN: | 2041-1723 |
| Popis: | 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. HMBG1 is a protein expressed in natural killer cells and is important in immunosurveillance. In this study, the authors show that HMGB1 binds to and inhibits PKM2, resulting in a block in aerobic glycolysis and ultimately cell death. |
| Databáze: | OpenAIRE |
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