Abstract
Intense interest in the 'Warburg effect' has been revived by the discovery that hypoxia-inducible factor 1 (HIF1) reprogrammes pyruvate oxidation to lactic acid conversion; lactic acid is the end product of fermentative glycolysis. The most aggressive and invasive cancers, which are often hypoxic, rely on exacerbated glycolysis to meet the increased demand for ATP and biosynthetic precursors and also rely on robust pH-regulating systems to combat the excessive generation of lactic and carbonic acids. In this Review, we present the key pH-regulating systems and synthesize recent advances in strategies that combine the disruption of pH control with bioenergetic mechanisms. We discuss the possibility of exploiting, in rapidly growing tumours, acute cell death by 'metabolic catastrophe'.
Publication types
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Research Support, Non-U.S. Gov't
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Review
MeSH terms
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Autophagy
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Bicarbonates / metabolism
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Carbonic Acid / metabolism
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Carbonic Anhydrases / metabolism
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Cation Transport Proteins / metabolism
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Energy Metabolism*
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Humans
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Hydrogen-Ion Concentration
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Hypoxia-Inducible Factor 1 / metabolism
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Lactic Acid / metabolism
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Monocarboxylic Acid Transporters / metabolism
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Muscle Proteins / metabolism
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Neoplasms / drug therapy*
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Neoplasms / metabolism*
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Protons*
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers / metabolism
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Symporters / metabolism
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Tumor Microenvironment
Substances
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Bicarbonates
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Cation Transport Proteins
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Hypoxia-Inducible Factor 1
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Monocarboxylic Acid Transporters
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Muscle Proteins
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Protons
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SLC16A4 protein, human
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SLC9A1 protein, human
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Sodium-Hydrogen Exchanger 1
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Sodium-Hydrogen Exchangers
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Symporters
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monocarboxylate transport protein 1
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Lactic Acid
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Carbonic Acid
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Carbonic Anhydrases