Metabolic Pathways in Tumours: Vulnerable Steps for a Therapy

Abstract

The adaptation of normal cells to physiological situations is fulfilled by metabolic changes that tumour cells have difficulty to perform. The enzymes involved being unable to take the adequate configuration. Thus, tumour cells rewire the system differently. They become dependent on ketolysis for producing acetyl-CoA and citrate in their Krebs cycle. Citrate feeds the cytosolic fatty acid synthesis pathway making lipid membranes for mitotic cells. In tumour cells, there are two bottle necks at the end of glycolysis, impairing the glycolytic supply of acetyl-|CoA, while the synthesis of fatty acids, has  turned off the degradation of fatty acid into acetyl-CoA. The shortage of acetyl-CoA for synthetizing citrate, is consequently compensated in tumours by a ketolytic acetyl-CoA supply. In addition, the exit of citrate in the cytosol, is supported by an inhibition of Aconitase, the second enzyme in the Krebs cycle.  In fact, the circuits used by tumour cells gives them an advantage, they plunder glucose and ketone body stores. However, the rewired system, has vulnerable points that are discussed for finding a possible therapy.