Brick by brick: metabolism and tumor cell growth
Introduction
Otto Warburg's demonstration that tumor cells rapidly use glucose and convert the majority of it to lactate is still the most fundamental and enduring observation in tumor metabolism [1, 2]. His work, which ushered in an era of study on tumor metabolism focused on the relationship between glycolysis and cellular bioenergetics, has been revisited and expanded by generations of tumor biologists. It is now accepted that a high rate of glucose metabolism, exploited clinically by 18FDG-PET scanning, is a metabolic hallmark of rapidly dividing cells, correlates closely with transformation, and accounts for a significant percentage of ATP generated during cell proliferation [3, 4, 5, 6•, 7]. Appreciation of the generality of the Warburg effect stimulated the broader concept that a ‘metabolic transformation’ is required for tumorigenesis. Research over the past few years has reinforced this idea, revealing the conservation of metabolic activities among diverse tumor types, and proving that oncogenic mutations can promote metabolic autonomy by driving nutrient uptake to levels that often exceed those required for cell growth and proliferation [8].
Aerobic glycolysis is just one component of the metabolic transformation. In order to engage in replicative division, a cell must duplicate its genome, proteins, and lipids and assemble the components into daughter cells; in short, it must become a factory for macromolecular biosynthesis. These activities require that cells take up extracellular nutrients like glucose and glutamine and allocate them into metabolic pathways that convert them into biosynthetic precursors (Figure 1). Tumor cells can achieve this phenotype through changes in the expression of enzymes that determine metabolic flux rates, including nutrient transporters and enzymes [8, 9, 10]. Current studies in tumor metabolism are revealing novel mechanisms for metabolic control, establishing which enzyme isoforms facilitate the tumor metabolic phenotype, and suggesting new targets for cancer therapy.
The ongoing challenge in tumor cell metabolism is to understand how individual pathways fit together into the global metabolic phenotype of cell growth. Here we discuss two biosynthetic activities required by proliferating tumor cells: production of ribose-5-phosphate for nucleotide biosynthesis and production of fatty acids for lipid biosynthesis. Nucleotide and lipid biosynthesis share three important characteristics. First, both use glucose as a carbon source. Second, both consume TCA cycle intermediates, imposing the need for a mechanism to replenish the cycle. Third, both require reductive power in the form of NADPH. In this review, we discuss emerging concepts in how proliferating tumor cells achieve high rates of nucleotide and lipid synthesis and propose a model in which glutamine metabolism satisfies crucial aspects of the metabolic transformation, allowing cells to use glucose carbon to build nucleic acid and lipid.
Section snippets
How do tumor cells divert glycolytic carbon toward ribose-5-phosphate synthesis?
To generate ribose 5-phosphate (R5P) for nucleotide biosynthesis, cells divert carbon from glycolysis into either the oxidative or non-oxidative arm of the pentose phosphate pathway. Oncogenes and tumor suppressors influence both pathways. The p53 target TP53-induced glycolysis and apoptosis regulator (TIGAR) suppresses glycolysis by decreasing levels of the phosphofructokinase-1 activator fructose-2,6-bisphosphate, increasing substrate delivery to the oxidative pathway [11••] (Figure 2a).
How do tumor cells synthesize fatty acids and lipids?
It has been more than 50 years since the first demonstration that tumors synthesize fatty acids from glucose (Figure 3), and subsequent studies have proven that interrupting fatty acid synthesis can be used as a chemotherapeutic strategy [27]. Tumor cells use fatty acids to modify membrane-targeted proteins and for bulk membrane synthesis, and therefore fatty acid synthesis influences cell signaling and growth. The latter may be crucial for tumorigenesis because most acyl groups in tumor lipids
How does glutamine metabolism support biosynthetic activities in tumor cells?
Glutamine metabolism can allow cells to meet both the anaplerotic and NADPH demands of growth. Since the 1950s, it has been clear that tumors consume large amounts of glutamine. The rate of consumption is not explained by protein synthesis because it exceeds the need for essential amino acids by 10-fold [49]. Later studies revealed rapid but partial glutamine oxidation and secretion of glutamine-derived carbon as lactate (Figure 3), establishing glutamine as an energy source in tumor cells [50
Conclusions
An enhanced biosynthetic capacity is a key feature of the metabolic transformation of tumor cells. The activities discussed here (synthesis of nucleotides and fatty acids, consumption of glucose and glutamine) are pervasive among tumors and tumor cell lines. It seems likely that these activities, particularly the use of glutamine as a source of both reductive power and anaplerosis, are general characteristics of cell growth and proliferation. Many questions remain as to how these activities are
References and recommended reading
Papers of particular interest, published within the annual period of review, have been highlighted as:
• of special interest
•• of outstanding interest
Acknowledgements
The authors thank members of the Thompson laboratory for critical reading of the manuscript. This work is supported by National Institutes of Health grants PO1 CA104838 (CBT) and K08 DK072565 (RJD).
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