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Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
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Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
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Journal Article
Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
2018
Overview
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
13
C-glucose and in vivo hyperpolarized
13
C-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.
Tumor cells can fuel their metabolism with lactate. Here the authors show that inhibition of mitochondrial pyruvate carrier (MPC) blocks extracellular lactate uptake by promoting intracellular pyruvate accumulation and inhibits oxidative metabolism, ultimately resulting in cytotoxicity and radiosensitization.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/1
/ 13/51
/ 13/89
/ 13/95
/ 14
/ 14/34
/ 14/63
/ 140/131
/ 140/58
/ 38
/ 38/109
/ 59
/ 64
/ 64/60
/ 96
/ Animals
/ Antineoplastic Agents - pharmacology
/ Cancer
/ Female
/ Glucose
/ Humanities and Social Sciences
/ Humans
/ Hypoxia
/ Ion Transport - drug effects
/ Kinases
/ Lactic Acid - pharmacokinetics
/ Male
/ Mice
/ Monocarboxylic Acid Transporters - genetics
/ Monocarboxylic Acid Transporters - physiology
/ Muscle Proteins - physiology
/ Radiation-Sensitizing Agents - pharmacology
/ Rats
/ RNA, Small Interfering - metabolism
/ Science
