304760.fig.004
Figure 4: Tetrameric M2 pyruvate kinase-driven fuel-generating (green panel) and dimeric M2 pyruvate kinase-driven biosynthetic precursor-generating (red panels) glycolysis (yellow panel) in cancer cells. Tumoral M2 pyruvate kinase exists in a dimeric inactive form that blocks pyruvate and ATP formation from glucose. It induces the accumulation of energy-rich phosphometabolites found upstream in the glycolytic pathway and off which biosynthetic processes may branch. Interconversion to the active tetrameric form of the enzyme may occur when the glucose supply is high, leading to a rise in fructose 1,6 bisphosphate which stimulates this tetrameric conversion. When glucose levels are high, cancer cells may then produce energy at the same time as supplying biosynthetic pathways. In this situation, the rise in glycolytic intermediary rich energy phosphometabolites results not from a block located downstream of their production but from an increased load of glycolysis by glucose. When glucose levels fall again, the subsequent decrease in fructose 1,6 bisphosphate results in recruitment of the dimeric inactive form of M2 pyruvate kinase. In this case, both energy and pyruvate production (and hence formation of lactate) by the tumor may derive from the catabolism of aminoacids such as glutamine and serine. The latter sets of metabolic reactions, by analogy with glycolysis for glucose to lactate production, are referred to as glutaminolysis and serinolysis, respectively. The supply of these aminoacids to the tumor is associated at distance with notably muscle proteolysis, explaining the progression of patients towards a cachectic state when the tumor gains in growth and development. Cachexy may be also favored by energy wasting associated to uncoupling of mitochondria in some cancer cell lines. Except with tumors such as insulinoma and hepatoma, for instance, no hypoglycaemia is, however, induced in patients since a sustained production of lactate is ensured by the tumor from these aminioacids. Lactate may be recycled to glucose by gluconeoformator cells, mainly hepatocytes (Cori’s cycle). Biosynthetic pathways branching off glycolysis include sialic acid, nucleic acid, aminoacid, ether glycerolipid, and ester glycerolipid anabolic pathways. The latter pathway is not emphasized here by inclusion in a red panel because in many cancer cell lines glycerol phosphate dehydrogenase is deficient thus reducing the availability of glycerol 3-phosphate and limiting incorporation of neoformed fatty acids into lipids. Fatty acid synthase is often overexpressed, and, along with the removal of fatty acids (known for immunosuppressive properties) outside the cell, it allows tumoral cells to cope with the massive rise in glycolysis-driven NADH and proton (H+) formation (glyceraldehyde 3-phosphate dehydrogenase step), avoiding excess acidification and consequent cell death. The threshold for reversible interconversion of tetrameric to dimeric M2 pyruvate kinase may be lowered by oncogenes in favor of the dimeric form. As mentioned in the text, the tetrameric active form is part of the glycolytic complex (a complex which groups most glycolytic enzymes for optimal metabolic function and energy production) whereas the dimeric form separates from this glycolytic complex.