The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration
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The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration. / Gdynia, Georg; Sauer, Sven W; Kopitz, Jürgen; Fuchs, Dominik; Duglova, Katarina; Ruppert, Thorsten; Miller, Matthias; Pahl, Jens; Cerwenka, Adelheid; Enders, Markus; Mairbäurl, Heimo; Kamiński, Marcin M; Penzel, Roland; Zhang, Christine; Fuller, Jonathan C; Wade, Rebecca C; Benner, Axel; Chang-Claude, Jenny; Brenner, Hermann; Hoffmeister, Michael; Zentgraf, Hanswalter; Schirmacher, Peter; Roth, Wilfried.
In: NAT COMMUN, Vol. 7, 07.03.2016, p. 10764.Research output: SCORING: Contribution to journal › SCORING: Journal article › Research › peer-review
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TY - JOUR
T1 - The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration
AU - Gdynia, Georg
AU - Sauer, Sven W
AU - Kopitz, Jürgen
AU - Fuchs, Dominik
AU - Duglova, Katarina
AU - Ruppert, Thorsten
AU - Miller, Matthias
AU - Pahl, Jens
AU - Cerwenka, Adelheid
AU - Enders, Markus
AU - Mairbäurl, Heimo
AU - Kamiński, Marcin M
AU - Penzel, Roland
AU - Zhang, Christine
AU - Fuller, Jonathan C
AU - Wade, Rebecca C
AU - Benner, Axel
AU - Chang-Claude, Jenny
AU - Brenner, Hermann
AU - Hoffmeister, Michael
AU - Zentgraf, Hanswalter
AU - Schirmacher, Peter
AU - Roth, Wilfried
PY - 2016/3/7
Y1 - 2016/3/7
N2 - 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.
AB - 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.
U2 - 10.1038/ncomms10764
DO - 10.1038/ncomms10764
M3 - SCORING: Journal article
C2 - 26948869
VL - 7
SP - 10764
JO - NAT COMMUN
JF - NAT COMMUN
SN - 2041-1723
ER -