In cancer, (Figure
1B) the enzymes PK, PDH, HSL, phosphorylase a, of body stores (Figure
1B left) are phosphorylated, via PKA activated by Gs receptors responding to catabolic hormones (glucagon, epinephrine). This situation mobilizes body stores as in starvation, compare to (Figure
1A left), which shows the effect of catabolic hormones. Tumor cells (Figure
1B right) display a hybrid situation, the enzymes PK, PDH are phosphorylated and blocked, via PKA and Gs receptors of tumor cells, as for catabolic hormone effects, while HSL, phosphorylase a, glycogen synthase are dephosphorylated, via PKB responding to tyrosine kinase receptors activated by insulin and IGF as in the case of anabolic hormone actions represented (Figure
1A right). In contrast to the “catabolic hormone situation” (Figure
1A left) tumor cells have an active citrate synthase, pulling the glycolytic flux in the glycolytic direction, to feed the condensation reaction of the Krebs cycle. How will tumor glycolysis reach the entry of the Krebs cycle and overcome the blockade of PK and PDH? This is not really a problem, since the enzyme PEPCK is fully reversible, and converts PEP, accumulated above the PK bottleneck, into OAA. The latter, is condensed with acetyl CoA coming from the mobilization of lipid stores (Figure
1B left and right). In tumors, the pyruvate resulting from alanine transamination gives lactate (Warburg effect) and NAD
+ required for glycolysis to proceed at the glyceraldehydephosphate dehydrogenase step (Figure
1B left and right). It follows then that the supply of pyruvate to pyruvate carboxylase is interrupted. However, in tumors, there is a downstream blockade in the Krebs cycle, below the level of citrate synthase, favoring the efflux of citrate from mitochondria. This citrate is then cleaved by cytosolic ATP citratelyase, providing acetyl CoA for fatty acids and triglyceride synthesis, while the other enzyme product, OAA, drives the transaminases in the direction found in neoglucogenesis, which then consume amino acids and glutamine. In tumors these amino acids are diverted for making proteins rather than feeding the neoglucogenic pathway (Figure
1B left and right). As for the urea cycle it is active in tumors, as it is the case in neoglucogenesis, but the argininosuccinate synthase step is blocked.