Autoregulation of H+/lactate efflux prevents monocarboxylate transport (MCT) inhibitors from reducing glycolytic lactic acid production
Menée à l'aide de lignées cellulaires d'adénocarcinome canalaire du pancréas, cette étude démontre que les inhibiteurs des transporteurs d'acides monocarboxyliques ne permettent pas de réduire de manière proportionnelle la production cellulaire d'acide lactique en raison de l'autorégulation des flux transmembranaires
Background : Pharmacological inhibition of membrane transporters is expected to reduce the flow of solutes, unless flux is restored (i.e., autoregulated) through a compensatory increase in the transmembrane driving force. Drugs acting on monocarboxylate transporters (MCTs) have been developed to disrupt glycolytic metabolism, but autoregulation would render such interventions ineffective. We evaluated whether small-molecule MCT inhibitors reduce cellular H+/lactate production. Methods : Cellular assays measured the relationship between MCT activity (expressed as membrane H+/lactate permeability; PHLac) and lactic acid production (inferred from H+ and lactate excretion; JHLac) in a panel of pancreatic ductal adenocarcinoma (PDAC) cells spanning a range of glycolytic phenotype. Results : MCT activity did not correlate with lactic acid production, indicating that it is not set by membrane permeability properties. MCT inhibitors did not proportionately reduce JHLac because of a compensatory increase in the transmembrane [lactate] driving force. JHLac was largely insensitive to [lactate], therefore its cytoplasmic build-up upon MCT inhibition does not hinder glycolytic production. Extracellular acidity, an MCT inhibitor, reduced JHLac but this was via cytoplasmic acidification blocking glycolytic enzymes. Conclusions : We provide mathematically verified evidence that pharmacological and physiological modulators of MCTs cannot proportionately reduce lactic acid production because of the stabilising effect of autoregulation on overall flux.