Disrupting proton dynamics and energy metabolism for cancer therapy View Full Text


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Article Info

DATE

2013-08-23

AUTHORS

Scott K. Parks, Johanna Chiche, Jacques Pouysségur

ABSTRACT

Key PointsIn 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), HCO3− transporters, lactate/H+ symporters (monocarboxylate transporter 1 (MCT1) and MCT4) and intracellular H+ pumps — are essential to maintain a permissive intracellular pH (pHi) 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. More... »

PAGES

611-623

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    http://scigraph.springernature.com/pub.10.1038/nrc3579

    DOI

    http://dx.doi.org/10.1038/nrc3579

    DIMENSIONS

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    PUBMED

    https://www.ncbi.nlm.nih.gov/pubmed/23969692


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