Disrupting proton dynamics and energy metabolism for cancer therapy

Key Points In rapidly growing cancer cells, oncogenes and hypoxia stimulate glycolytic metabolism, which generates increased amounts of lactic and carbonic acids. Several pH-regulating systems — Na + /H + exchangers (NHEs), carbonic anhydrases (CAIX and CAXII), HCO 3 − transporters, lactate/H + symporters (monocarboxylate transporter 1 (MCT1) and MCT4) and intracellular H + pumps — are essential to maintain a permissive intracellular pH (pH i ) to optimize bioenergetic metabolism, cell cycle progression, growth and survival. Cells lacking pH-regulating capabilities can enter growth arrest or can be 'killed' by H + . Targeting pH-regulating proteins in isolation (NHE1, CAs, MCTs and H + pumps) impairs tumour progression. Targeting the export of lactic acid from tumour cells (by disrupting MCTs) reduces glycolysis and growth rates, thus sensitizing tumour cells to treatment with mitochondrial complex I inhibitors (such as metformin and phenformin). We propose the development of an acute 'metabolic knife' treatment that combines targeting of pH control and ATP-driven metabolism to eradicate rapidly growing glycolytic tumours. Because of the increased production of acids, the altered metabolism of tumour cells renders them especially reliant on pH-regulatory systems that ensure that the intracellular pH does not decrease too much. This Review discusses the interplay among metabolism, hypoxia and pH regulation and whether pH-regulatory systems can be targeted for anticancer therapy. 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'.