Brick by brick: metabolism and tumor cell growth

Abstract

Tumor cells display increased metabolic autonomy in comparison to non-transformed cells, taking up nutrients and metabolizing them in pathways that support growth and proliferation. Classical work in tumor cell metabolism focused on bioenergetics, particularly enhanced glycolysis and suppressed oxidative phosphorylation (the 'Warburg effect'). But the biosynthetic activities required to create daughter cells are equally important for tumor growth, and recent studies are now bringing these pathways into focus. In this review, we discuss how tumor cells achieve high rates of nucleotide and fatty acid synthesis, how oncogenes and tumor suppressors influence these activities, and how glutamine metabolism enables macromolecular synthesis in proliferating cells.

Figure 1. Tumor cells obtain biosynthetic precursors from glucose and glutamine metabolism

Glucose and glutamine, the two most abundant extracellular nutrients, contribute carbon for the synthesis of the three major classes of macromolecules (nucleic acids, lipids and proteins) in proliferating tumor cells. Biosynthesis of purines and pyrimidines utilizes ribose 5-phosphate (R5P) produced from diversion of glycolytic intermediates into the oxidative and non-oxidative arms of the pentose phosphate pathway, and nonessential amino acids derived from glucose and glutamine. Fatty acid synthesis, used to produce cellular lipids, requires acetyl-CoA (Ac-CoA), most of which is generated from glucose and transferred from the mitochondria to the cytoplasm via citrate. Protein synthesis requires amino acids, tRNAs and ribosomes (proteins and rRNAs). Both glucose and glutamine are used to generate these molecules. In addition to its role as a carbon source, glutamine also donates nitrogen to nucleotide and amino acid synthesis. Abbreviations: P, phosphate; GA3P, glyceraldehyde 3-phosphate; 3-PG, 3-phosphoglycerate; PRPP, phosphoribosyl pyrophosphate; Mal-CoA, malonyl-CoA.

Figure 2. A model for control of oxidative and non-oxidative pentose phosphate flux

A, Activation of p53 by DNA damage enhances oxidative pentose phosphate flux via effects on TIGAR and PGM. As a result, cells generate NADPH and R5P for nucleotide synthesis and DNA repair. B, Tumors and tumor cell lines, perhaps through the effects of oncogenic mutations, generally express PK-M2 and TKTL1. Dimeric PK-M2 enzyme has sub-maximal activity and allows glycolytic intermediates to accumulate, facilitating TKTL1-catalyzed non-oxidative pentose phosphate flux and suppressing oxidative flux. As a result, there is a mismatch between the amount of R5P and NADPH generated by total pentose phosphate activity. Abbreviations: Glc, glucose; G6P, glucose 6-phosphate; F6P, fructose 6-phosphate; F1,6biP, fructose 1,6-bisphosphate; F2,6biP, fructose 2,6-bisphosphate; DHAP, dihydroxyacetone phosphate; GA3P, glyceraldehyde 3-phosphate; PEP, phosphoenolpyruvate; R5P, ribose 5-phosphate; G6PD, glucose 6-phosphate dehydrogenase; PFK1, phosphofructokinase-1; PGM, phosphoglucomutase; TIGAR, TP53-induced glycolysis and apoptosis regulator; PK-M2, pyruvate kinase M2; TKTL1, transketolase-like 1.

Figure 3. Glutamine metabolism allows tumor cells to sustain TCA cycle activity and produce NADPH during proliferation

Glucose provides cells with a source of Ac-CoA for fatty acid synthesis (blue arrows), which is enhanced in tumors due to oncogene-driven expression of the lipogenic enzymes ATP-citrate lyase (ACL), acetyl-CoA carboxylase-1 (ACC) and fatty acid synthase (FAS). However, continuous citrate export introduces a deficit to the TCA cycle, and this must be replaced by an anaplerotic flux in order for fatty acid synthesis and cell growth to continue. Metabolism of glutamine (red arrows) provides a mitochondrial oxaloacetate pool for continued citrate synthesis. After citrate cleavage by ACL in the cytoplasm, the resulting oxaloacetate can be converted to malate and ultimately lactate by the low NAD+/NADH ratio created by rapid glycolysis. Glutamine may also be converted to lactate if mitochondrial malate is exported to the cytoplasm and decarboxylated by malic enzyme (ME). This pathway appears to be a major source of NADPH for fatty acid synthesis and other activities in tumor cells. Abbreviations: Ac-CoA, acetyl-CoA; Mal-CoA, malonyl-CoA; MDH, malate dehydrogenase; LDH-A, lactate dehydrogenase-A; GLS, glutaminase; SREBP-1, sterol response element binding protein-1.