Journal Article

DKFZ-2017-02005

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png The HMGB1 protein induces a metabolic type of tumour cell death by blocking aerobic respiration.

Gdynia, G. P. (First author)DKFZ* ; Sauer, S. W. ; Kopitz, J.DKFZ* ; Fuchs, D. ; Duglova, K. ; Ruppert, T. ; Miller, M.DKFZ* ; Pahl, J.DKFZ* ; Cerwenka, A.DKFZ* ; Enders, M. ; Mairbäurl, H. ; Kamiński, M. M.DKFZ* ; Penzel, R. ; Zhang, C. ; Fuller, J. C. ; Wade, R. C. ; Benner, A.DKFZ* ; Chang, J.DKFZ* ; Brenner, H.DKFZ* ; Hoffmeister, M.DKFZ* ; Zentgraf, H.DKFZ* ; Schirmacher, P. ; Roth, W. (Last author)DKFZ*

2016
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/ncomms10764

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.

Keyword(s): Carrier Proteins ; HMGB1 Protein ; Membrane Proteins ; Thyroid Hormones ; thyroid hormone-binding proteins ; Glucose

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Contributing Institute(s):

1. Biostatistik (C060)
2. Epidemiologie von Krebserkrankungen (C020)
3. Klinische Epidemiologie und Alternsforschung (C070)
4. Nachwuchsgruppe Angeborene Immunität (D080)
5. Präventive Onkologie (G110)
6. Gentherapie von Tumoren (G105)
7. Molekulare Tumorpathologie (G150)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2016

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Database coverage:
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