Key Points
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Multiple molecular mechanisms, both intrinsic and extrinsic, converge to alter core cellular metabolism and provide support for the three basic needs of dividing cells: rapid ATP generation to maintain energy status; increased biosynthesis of macromolecules; and tightened maintenance of appropriate cellular redox status. Metabolic changes are a common feature of cancerous tissues, although it is unclear to what extent these metabolic changes are important in low-grade slow growing tumours.
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The best characterized metabolic phenotype observed in tumour cells is the Warburg effect, which is a shift from ATP generation through oxidative phosphorylation to ATP generation through glycolysis, even under normal oxygen concentrations. This effect is regulated by the PI3K, hypoxia-indicible factor (HIF), p53, MYC and AMP-activated protein kinase (AMPK)–liver kinase B1 (LKB1) pathways.
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Metabolic adaptation in tumours extends beyond the Warburg effect. It is becoming clear that alterations to metabolism balance the need of the cell for energy with its equally important need for macromolecular building blocks and maintenance of redox balance. To this end, a key molecule produced as a result of altered cancer metabolism is reduced nicotinamide adenine dinucleotide phosphate (NADPH), which functions as a cofactor and provides reducing power in many enzymatic reactions that are crucial for macromolecular biosynthesis. NADPH is also an antioxidant and forms part of the defence against reactive oxygen species (ROS) that are produced during rapid proliferation.
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High levels of ROS can cause damage to macromolecules, which can induce senescence and apoptosis. Cells counteract the detrimental effects of ROS by producing antioxidant molecules, such as reduced glutathione (GSH) and thioredoxin (TRX). Several of these antioxidant systems, including GSH and TRX, rely on the reducing power of NADPH to maintain their activities.
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In addition to the genetic changes that alter tumour cell metabolism, the abnormal tumour microenvironment — such as hypoxia, pH and low glucose concentrations — have a major role in determining the metabolic phenotype of tumour cells.
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Mutations in oncogenes and tumour suppressor genes cause alterations to multiple intracellular signalling pathways that affect tumour cell metabolism and re-engineer it to allow enhanced survival and growth.
Abstract
Interest in the topic of tumour metabolism has waxed and waned over the past century of cancer research. The early observations of Warburg and his contemporaries established that there are fundamental differences in the central metabolic pathways operating in malignant tissue. However, the initial hypotheses that were based on these observations proved inadequate to explain tumorigenesis, and the oncogene revolution pushed tumour metabolism to the margins of cancer research. In recent years, interest has been renewed as it has become clear that many of the signalling pathways that are affected by genetic mutations and the tumour microenvironment have a profound effect on core metabolism, making this topic once again one of the most intense areas of research in cancer biology.
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The authors would like to thank M. Saunders for scientific editing of the Review.
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Glossary
- Redox status
-
Balance of the reduced state versus the oxidized state of a biochemical system. This balance is influenced by the level of reactive oxygen and nitrogen species (ROS and RNS) relative to the capacity of antioxidant systems to eliminate ROS and RNS.
- Oxidative phosphorylation
-
Oxygen-dependent process coupling the oxidation of macromolecules and the electron transport chain with ATP synthesis. In eukaryotic cells, it occurs within the mitochondria and is a source of ROS production.
- Glycolysis
-
Oxygen-independent metabolism of glucose and other sugars into pyruvate to produce energy in the form of ATP and intermediate substrates for other metabolic pathways.
- Pentose phosphate pathway
-
PPP. Biochemical pathway converting glucose into substrates for nucleotide biosynthesis and redox control, such as ribose and NADPH. Owing to multiple connections to the glycolytic pathway, the PPP can operate in various modes to allow the production of NADPH and/or ribose as required.
- Macromolecular biosynthesis
-
Biochemical synthesis of the carbohydrates, nucleotides, proteins and lipids that make up cells and tissues. These pathways require energy, reducing power and appropriate substrates.
- Reduced nicotinamide adenine dinucleotide phosphate
-
NADPH. Cofactor that drives anabolic biochemical reactions and provides reducing capacity to combat oxidative stress.
- 2-hydroxyglutarate
-
2-HG. A dicarboxylic acid metabolite produced from αKG by the NADPH-dependent reaction of the mutated forms of IDH1 and IDH2. It is also produced at low levels by other enzymes.
- Parkinson's disease
-
A neurodegenerative disorder affecting the CNS, which is characterized by muscle rigidity and the onset of tremors.
- Amyotrophic lateral sclerosis
-
ALS. Also known as Lou Gehrigs disease; it occurs owing to the degeneration of the CNS and leads to the inability to control muscles and eventual muscle atrophy.
- Glutaminolysis
-
The catabolic metabolism of glutamine, which yields substrates that replenish the TCA cycle, produce GSH and supply building blocks for amino acid and nucleotide synthesis.
- Anapleurosis
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Category of reactions that serve to replenish the intermediate substrates of an anabolic biochemical pathway, especially important in the TCA cycle.
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Cairns, R., Harris, I. & Mak, T. Regulation of cancer cell metabolism. Nat Rev Cancer 11, 85–95 (2011). https://doi.org/10.1038/nrc2981
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DOI: https://doi.org/10.1038/nrc2981
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