The HMGB1 protein induces a metabolic type of tumor cell death by blocking aerobic respiration

The HMGB1 protein induces a metabolic type of tumor cell death by blocking aerobic respiration

The high-mobility group box 1 (HMGB1) protein is a ubiquitously expressed cytokine known for its pro-inflammatory effects on release from macrophages. In the setting of cancer, HMGB1 signalling through its innate immune system receptors TLR2 and TLR4 (toll-like receptors 2 and 4) is important for an antitumor immune response in breast cancer patients. The release of high amounts of HMGB1, in particular from natural killer (NK) cells, is pivotal for dendritic cell activation4 and chemotaxis In addition, HMGB1 exhibits striking antimicrobial activity resulting in rapid killing of bacteria.

However, endogenous HMGB1 is also intricately involved in the energy metabolism of cells and organs. HMGB1 knock-out mice are unable to utilize glycogen storage pools in hepatocytes and die due to perinatal hypoglycaemia. Glucose temporarily rescues the animals, but the mice succumb several days later due to severe atrophy of inner organs, muscle and fatty tissue.  Both lack and excess of HMGB1 severely affects cellular energy metabolism.

Recently, authors 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. One of the main targets of HMGB1 turned out to be the mitochondrial energy metabolism as tumor cells devoid of a functioning mitochondrial respiratory chain were resistant to HMGB1 cytotoxicity.

 In this study, they investigated whether the cytotoxic activity of HMGB1 plays a role in antitumor defense mechanisms. The data provide evidence that the innate immune system employs specific forms of ‘metabolic weapons’ to target cancer cells. HMGB1 physically interacts with the pyruvate kinase (PK) isoform M2 resulting in a rapid blockage of glucose-dependent 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, authors 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.