Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects

Cyril Corbet (), Estelle Bastien, Nihed Draoui, Bastien Doix, Lionel Mignion, Bénédicte F. Jordan, Arnaud Marchand, Jean-Christophe Vanherck, Patrick Chaltin, Olivier Schakman, Holger M. Becker, Olivier Riant and Olivier Feron ()
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Cyril Corbet: Institut de Recherche Expérimentale et Clinique (IREC)
Estelle Bastien: Institut de Recherche Expérimentale et Clinique (IREC)
Nihed Draoui: Institut de Recherche Expérimentale et Clinique (IREC)
Bastien Doix: Institut de Recherche Expérimentale et Clinique (IREC)
Lionel Mignion: Biomedical Magnetic Resonance Research Group
Bénédicte F. Jordan: Biomedical Magnetic Resonance Research Group
Arnaud Marchand: Center for Drug Design and Discovery (CD3) KU Leuven
Jean-Christophe Vanherck: Center for Drug Design and Discovery (CD3) KU Leuven
Patrick Chaltin: Center for Drug Design and Discovery (CD3) KU Leuven
Olivier Schakman: Université catholique de Louvain
Holger M. Becker: TU Kaiserslautern
Olivier Riant: Université catholique de Louvain
Olivier Feron: Institut de Recherche Expérimentale et Clinique (IREC)

Nature Communications, 2018, vol. 9, issue 1, 1-11

Abstract: Abstract Lactate exchange between glycolytic and oxidative cancer cells is proposed to optimize tumor growth. Blocking lactate uptake through monocarboxylate transporter 1 (MCT1) represents an attractive therapeutic strategy but may stimulate glucose consumption by oxidative cancer cells. We report here that inhibition of mitochondrial pyruvate carrier (MPC) activity fulfils the tasks of blocking lactate use while preventing glucose oxidative metabolism. Using in vitro 13C-glucose and in vivo hyperpolarized 13C-pyruvate, we identify 7ACC2 as a potent inhibitor of mitochondrial pyruvate transport which consecutively blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation. Also, while in spheroids MCT1 inhibition leads to cytostatic effects, MPC activity inhibition induces cytotoxic effects together with glycolysis stimulation and uncompensated inhibition of mitochondrial respiration. Hypoxia reduction obtained with 7ACC2 is further shown to sensitize tumor xenografts to radiotherapy. This study positions MPC as a control point for lactate metabolism and expands on the anticancer potential of MPC inhibition.

Date: 2018
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Persistent link: https://EconPapers.repec.org/RePEc:nat:natcom:v:9:y:2018:i:1:d:10.1038_s41467-018-03525-0

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DOI: 10.1038/s41467-018-03525-0

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