Interrogating the Lactate Dehydrogenase Tetramerization Site Using (Stapled) Peptides.

Lactate dehydrogenases (LDHs) are tetrameric enzymes of major significance in cancer metabolism as well as promising targets for cancer therapy. However, their wide and polar catalytic sites make them a challenging target for orthosteric inhibition. In this work, we conceived to target LDH tetramerization sites with the ambition of disrupting their oligomeric state.

Lactate Dehydrogenase B Controls Lysosome Activity and Autophagy in Cancer.

Metabolic adaptability is essential for tumor progression and includes cooperation between cancer cells with different metabolic phenotypes. Optimal glucose supply to glycolytic cancer cells occurs when oxidative cancer cells use lactate preferentially to glucose. However, using lactate instead of glucose mimics glucose deprivation, and glucose starvation induces autophagy.

Lactate does not activate NF-κB in oxidative tumor cells.

The lactate anion is currently emerging as an oncometabolite. Lactate, produced and exported by glycolytic and glutaminolytic cells in tumors, can be recycled as an oxidative fuel by oxidative tumors cells. Independently of hypoxia, it can also activate transcription factor hypoxia-inducible factor-1 (HIF-1) in tumor and endothelial cells, promoting angiogenesis.

A mitochondrial switch promotes tumor metastasis.

Metastatic progression of cancer is associated with poor outcome, and here we examine metabolic changes underlying this process. Although aerobic glycolysis is known to promote metastasis, we have now identified a different switch primarily affecting mitochondria. The switch involves overload of the electron transport chain (ETC) with preserved mitochondrial functions but increased mitochondrial superoxide production.