Gdynia 2016 Nat Commun

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Gdynia G, Sauer SW, Kopitz J, Fuchs D, Duglova K, Ruppert T, Miller M, Pahl J, Cerwenka A, Enders M, Mairbäurl H, Kamiński MM, Penzel R, Zhang C, Fuller JC, Wade RC, Benner A, Chang-Claude J, Brenner H, Hoffmeister M, Zentgraf H, Schirmacher P, Roth W (2016) The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. Nat Commun 7:10764.

» PMID: 26948869 Open Access

Gdynia G, Sauer SW, Kopitz J, Fuchs D, Duglova K, Ruppert T, Miller M, Pahl J, Cerwenka A, Enders M, Mairbaeurl H, Kaminski MM, Penzel R, Zhang C, Fuller JC, Wade RC, Benner A, Chang-Claude J, Brenner H, Hoffmeister M, Zentgraf H, Schirmacher P, Roth W (2016) Nat Commun

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.

Keywords: Human colorectal adenocarcinoma SW480 cells, Human colon carcinoma HCT116 cells, Human colorectal adenocarcinomaHT29 cells

O2k-Network Lab: DE Heidelberg Mairbaeurl H


Labels: MiParea: Respiration, Pharmacology;toxicology  Pathology: Cancer  Stress:Cell death  Organism: Human  Tissue;cell: Endothelial;epithelial;mesothelial cell, Other cell lines  Preparation: Permeabilized cells 


Coupling state: ROUTINE  Pathway: ROX  HRR: Oxygraph-2k 

2016-05