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RESEARCH PRODUCT
The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration
Peter SchirmacherPeter SchirmacherPeter SchirmacherThorsten RuppertJens PahlAxel BennerJonathan C. FullerKatarina DuglovaJenny Chang-claudeRoland PenzelAdelheid CerwenkaHanswalter ZentgrafHermann BrennerHeimo MairbäurlMichael HoffmeisterGeorg GdyniaMarcin KamińskiWilfried RothDominik FuchsMarkus EndersRebecca C. WadeRebecca C. WadeRebecca C. WadeSven W. SauerJürgen KopitzMatthias MillerChristine ZhangChristine Zhangsubject
0301 basic medicineProgrammed cell deathThyroid HormonesCellular respirationScienceCell RespirationMalic enzymeGeneral Physics and Astronomychemical and pharmacologic phenomenaPKM2BiologyGeneral Biochemistry Genetics and Molecular BiologyArticle03 medical and health sciencesCell Line TumorHumansGlycolysisHMGB1 ProteinMultidisciplinaryGlutaminolysisCell DeathQMembrane ProteinsGeneral ChemistryCell biology030104 developmental biologyGlucoseCancer cellColonic NeoplasmsCarrier ProteinsGlycolysisPyruvate kinasedescription
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.
| year | journal | country | edition | language |
|---|---|---|---|---|
| 2016-03-01 | Nature Communications |