2. Academic Validation
  3. Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects

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

  • Nat Commun. 2018 Mar 23;9(1):1208. doi: 10.1038/s41467-018-03525-0.
Cyril Corbet 1,  Estelle Bastien 2,  Nihed Draoui 2 3,  Bastien Doix 2,  Lionel Mignion 4,  Bénédicte F Jordan 4,  Arnaud Marchand 5,  Jean-Christophe Vanherck 5,  Patrick Chaltin 5,  Olivier Schakman 6,  Holger M Becker 7 8,  Olivier Riant 9,  Olivier Feron 10
Affiliations

Affiliations

  • 1 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 53 Avenue Mounier B1.53.09, Brussels, B-1200, Belgium. cyril.corbet@uclouvain.be.
  • 2 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 53 Avenue Mounier B1.53.09, Brussels, B-1200, Belgium.
  • 3 Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, and Vesalius Research Center, VIB, Herestraat 49 box 912, B-3000, Leuven, Belgium.
  • 4 Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Université catholique de Louvain, 73 Avenue Mounier, REMA 73.08, Brussels, B-1200, Belgium.
  • 5 CISTIM Leuven, Center for Drug Design and Discovery (CD3) KU Leuven, Gaston Geenslaan 2, Heverlee, 3001, Belgium.
  • 6 Laboratory of Cell Physiology, Institute of Neuroscience, Université catholique de Louvain, Brussels, B-1200, Belgium.
  • 7 Division of Zoology/Membrane Transport, FB Biologie, TU Kaiserslautern, P.O. Box 3049, Kaiserslautern, D-67653, Germany.
  • 8 Institute of Physiological Chemistry, University of Veterinary Medicine Hannover, Bünteweg 17, Hannover, D-30559, Germany.
  • 9 Institute of Condensed Matter and Nanosciences, MOST division, Place Louis Pasteur, Université catholique de Louvain, Louvain-la-Neuve, B-1348, Belgium.
  • 10 Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, 53 Avenue Mounier B1.53.09, Brussels, B-1200, Belgium. olivier.feron@uclouvain.be.
PMID: 29572438 DOI: 10.1038/s41467-018-03525-0
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z