Regulation of cancer cell metabolism

• Published in: Nature reviews. Cancer Vol. 11; no. 2; pp. 85 - 95
• Main Authors: Mak, Tak W, Cairns, Rob A, Harris, Isaac S
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01-02-2011; Nature Publishing Group
• Subjects: 631/67/2327; 631/67/327; 631/80/86; Biomedical and Life Sciences; Biomedicine; Cancer; Cancer cells; Cancer Research; Cell Transformation, Neoplastic - genetics; Cell Transformation, Neoplastic - metabolism; Gene Expression Regulation, Neoplastic; Gene mutations; Gene Regulatory Networks; Genetic aspects; Health aspects; Humans; Intracellular Signaling Peptides and Proteins - metabolism; Metabolic pathways; Metabolism; Microenvironments; Mutation; Neoplasms - genetics; Neoplasms - metabolism; Oncogenes; Oxidation-Reduction; Physiological aspects; review-article; Signal Transduction; Transcription Factors - metabolism; Tumorigenesis; Canada
• ISSN: 1474-175X; 1474-1768
• DOI: 10.1038/nrc2981

Key Points
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.
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.
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.
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.
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.
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.
Fundamental differences in the regulation of central metabolic pathways exist between tumours and normal tissue. This Review discusses how the Warburg effect is still applicable to our view of cancer metabolism and new advances in understanding beyond this hypothesis, including regulating anapleurosis and the redox balance.
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.