The molecular determinants of de novo nucleotide biosynthesis in cancer cells

Abstract

Tumor cells increase the use of anabolic pathways to satisfy the metabolic requirements associated with a high growth rate. Transformed cells take up and metabolize nutrients such as glucose and glutamine at high levels that support anabolic growth. Oncogenic signaling through the PI3K/Akt and Myc pathways directly control glucose and glutamine uptake, respectively. In order to achieve elevated rates of nucleotide biosynthesis, neoplastic cells must divert carbon from PI3K/Akt-induced glycolytic flux into the nonoxidative branch of the pentose phosphate pathway to generate ribose-5-phosphate. This redirection of glucose catabolism appears to be regulated by cytoplasmic tyrosine kinases. Myc-induced glutamine metabolism also increases the abundance and activity of different rate-limiting enzymes that produce the molecular precursors required for de novo nucleotide synthesis. In this review, we will focus on recent progress in understanding how glucose and glutamine metabolism is redirected by oncogenes in order to support de novo nucleotide biosynthesis during proliferation and how metabolic reprogramming can be potentially exploited in the development of new cancer therapies.

Figure 1

Regulation of glycolysis, glutaminolysis and de novo nucleotide biosynthesis in tumor cells. Oncogenic activation of the PI3K/Akt and Myc pathways promotes glucose and glutamine uptake and catabolism. Tumor cells obtain precursors (in pink rectangles) including ribose 5-phosphate, glycine, glutamine, aspartate and NADPH for de novo biosynthesis from glucose and glutamine metabolism. Increased glucose uptake and PFK-1 activity by the PI3K/Akt pathway, inactivation of PK-M2 by p-Tyr signaling, as well as HIF-1-induced TKT activation allows glycolytic intermediates to enter the non-oxidative PPP for ribose 5-phosphate production in tumor cells. Hatched lines indicate that the oxidative arm of PPP is not the main pathway for ribose 5-phosphate or NADPH production in tumor cells. Glutamine is converted to lactate if mitochondrial malate is exported into the cytoplasm and decarboxylated to produce pyruvate by malic enzyme (ME). The glutaminolysis pathway and the reaction catalyzed by cytosolic isocitrate dehydrogenase (ICD) may serve as the major sources of NADPH for de novo nucleotide biosynthesis in tumor cells [9,52,53]. In addition to its role in providing tumor cells with NADPH, Myc also directly regulates several genes encoding key enzymes in the purine and pyrimidine biosynthetic pathway. Abbreviations: P, phosphate; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6BP, fructose 1,6-bisphosphate; GA3P, glyceraldehyde 3-phosphate; DHAP, dihydroxyacetone phosphate; 3-PG, 3-phosphoglycerate; PEP, phosphoenolpyruvate; OAA, oxaloacetate; G6PD, glucose 6-phosphate dehydrogenase; PFK-1, phosphofructokinase-1; TKT, transketolase; PK-M2, pyruvate kinase M2; LDHA, lactate dehydrogenase A; ME, malic enzyme; ICD, isocitrate dehydrogenase.