Hypoxia-induced mobilization of NHE6 to the plasma membrane triggers endosome hyperacidification and chemoresistance

Fabrice Lucien, Pierre-Paul Pelletier, Roxane R. Lavoie, Jean-Michel Lacroix, Sébastien Roy, Jean-Luc Parent, Dominique Arsenault, Kelly Harper and Claire M. Dubois ()
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Fabrice Lucien: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Pierre-Paul Pelletier: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Roxane R. Lavoie: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Jean-Michel Lacroix: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Sébastien Roy: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Jean-Luc Parent: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Dominique Arsenault: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Kelly Harper: Faculty of Medicine and Health Sciences, Université de Sherbrooke
Claire M. Dubois: Faculty of Medicine and Health Sciences, Université de Sherbrooke

Nature Communications, 2017, vol. 8, issue 1, 1-15

Abstract: Abstract The pH-dependent partitioning of chemotherapeutic drugs is a fundamental yet understudied drug distribution mechanism that may underlie the low success rates of current approaches to counter multidrug resistance (MDR). This mechanism is influenced by the hypoxic tumour microenvironment and results in selective trapping of weakly basic drugs into acidified compartments such as the extracellular environment. Here we report that hypoxia not only leads to acidification of the tumour microenvironment but also induces endosome hyperacidification. The acidity of the vesicular lumen, together with the alkaline pH of the cytoplasm, gives rise to a strong intracellular pH gradient that drives intravesicular drug trapping and chemoresistance. Endosome hyperacidification is due to the relocalization of the Na+/H+ exchanger isoform 6 (NHE6) from endosomes to the plasma membrane, an event that involves binding of NHE6 to the activated protein kinase C–receptor for activated C kinase 1 complex. These findings reveal a novel mechanism of hypoxia-induced MDR that involves the aberrant intracellular distribution of NHE6.

Date: 2017
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DOI: 10.1038/ncomms15884

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