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Interruption of lactate uptake by inhibiting mitochondrial pyruvate transport unravels direct antitumor and radiosensitizing effects
- Source :
- Nature Communications, Nature Communications, Vol 9, Iss 1, Pp 1-11 (2018), Nature Communications, Vol. 9, no.1, p. 1208 (2018)
- Publication Year :
- 2018
-
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.<br />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.
- Subjects :
- 0301 basic medicine
Male
Radiation-Sensitizing Agents
Journal Club
General Physics and Astronomy
Muscle Proteins
Mitochondrion
Pharmacology
chemistry.chemical_compound
Mice
Xenopus laevis
Neoplasms
Mitochondrial pyruvate transport
Pyruvic Acid
Glycolysis
RNA, Small Interfering
lcsh:Science
Multidisciplinary
biology
Symporters
3. Good health
Lactic acid
Mitochondria
Monocarboxylate transporter 1
MCF-7 Cells
Female
Monocarboxylic Acid Transporters
Science
Antineoplastic Agents
Oxidative phosphorylation
Thiophenes
Article
General Biochemistry, Genetics and Molecular Biology
03 medical and health sciences
Cell Line, Tumor
Animals
Humans
Gene Silencing
Lactic Acid
Pyruvates
Uracil
Ion Transport
Biological Transport
General Chemistry
Rats
Citric acid cycle
Mice, Inbred C57BL
Oxygen
030104 developmental biology
Glucose
chemistry
biology.protein
lcsh:Q
Pyruvic acid
Neoplasm Transplantation
Subjects
Details
- ISSN :
- 20411723
- Database :
- OpenAIRE
- Journal :
- Nature Communications
- Accession number :
- edsair.doi.dedup.....e1fad061cdbdcc2a126f4de33bc80499
- Full Text :
- https://doi.org/10.1038/s41467-018-03525-0