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.
Highlights
The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense
We described that HMGB1 induces a distinct form of necrotic cell death in cancer cells which differed from the classical cell death entities known so far[9]
We recently described that recombinant human HMGB1 efficiently induces a novel form of cell death in tumour cells[9]
Summary
The high-mobility group box 1 (HMGB1) protein has a central role in immunological antitumour defense. HMGB1 allosterically inhibits the tetrameric pyruvate kinase isoform M2, 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. Ex vivo incubation of murine muscle tissue with HMGB1 leads to rapid exhaustion of muscle fibres, and elevated HMGB1 concentrations are found in the myoplasm of patients suffering from polymyositis[8] Both lack and excess of HMGB1 severely affects cellular energy metabolism. Secreted HMGB1 can kill cancer cells by causing a brisk metabolic shift restricting their energy supply to glycolysis. This establishes a link between innate tumour defense and tumour metabolism
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