Monocarboxylate transporters in the brain and in cancer

https://doi.org/10.1016/j.bbamcr.2016.03.013Get rights and content
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Abstract

Monocarboxylate transporters (MCTs) constitute a family of 14 members among which MCT1–4 facilitate the passive transport of monocarboxylates such as lactate, pyruvate and ketone bodies together with protons across cell membranes. Their anchorage and activity at the plasma membrane requires interaction with chaperon protein such as basigin/CD147 and embigin/gp70. MCT1–4 are expressed in different tissues where they play important roles in physiological and pathological processes. This review focuses on the brain and on cancer. In the brain, MCTs control the delivery of lactate, produced by astrocytes, to neurons, where it is used as an oxidative fuel. Consequently, MCT dysfunctions are associated with pathologies of the central nervous system encompassing neurodegeneration and cognitive defects, epilepsy and metabolic disorders. In tumors, MCTs control the exchange of lactate and other monocarboxylates between glycolytic and oxidative cancer cells, between stromal and cancer cells and between glycolytic cells and endothelial cells. Lactate is not only a metabolic waste for glycolytic cells and a metabolic fuel for oxidative cells, but it also behaves as a signaling agent that promotes angiogenesis and as an immunosuppressive metabolite. Because MCTs gate the activities of lactate, drugs targeting these transporters have been developed that could constitute new anticancer treatments. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Abbreviations

AMPA
α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid
AMPK
AMP-activated protein kinase
BDNF
brain-derived neurotrophic factor
bFGF
basic fibroblast growth factor
CA
carbonic anhydrase
CAF
cancer-associated fibroblast
CHC
α-cyano-4-hydroxycinnamate
CN
calcineurin
CTL
cytolytic T lymphocyte
DBDS
4,4′-dibenzamidostilbene-2,2′-disulphonate
DC
dendritic cell
DIDS
4,4′-diisothiocyano-2,2′-stilbenedisulfonic acid
EAAT1
excitatory amino acid transporter 1
glpT
glycerol phosphate transporter
IGF1
insulin-like growth factor 1
IkBα
inhibitor of NF-kB α
Iκκβ
inhibitor of NF-κB kinase β
LDH
lactate dehydrogenase
MCP
monocarboxylate porter
MCT
monocarboxylate transporter
MDSC
myeloid-derived suppressor cell
MFS
major facilitator superfamily
MPTP
1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine
NFAT
nuclear factor of activated T cells
NF-kB
nuclear factor-kB
NK
natural killer (cell)
NMDA
N-methyl-D-aspartate
NSCLC
non-small cell lung cancer
OXPHOS
oxidative phosphorylation
pCMBS
p-chloromercuribenzene sulphonate
PHD
prolylhydroxylase
ROS
reactive oxygen species
TM
transmembrane (domain)
VEGF
vascular endothelial growth factor

Keywords

Metabolic cooperation
Lactate shuttle
Neurons
Astrocytes
Tumor cells
Tumor microenvironment

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This article is part of a Special Issue entitled: Mitochondrial Channels edited by Jean-Claude Martinou.

1

These authors contributed equally to this manuscript.