Monocarboxylate transporters in the brain and in cancer

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.

Keywords: Astrocytes; Lactate shuttle; Metabolic cooperation; Neurons; Tumor cells; Tumor microenvironment.

Fig. 1

Model depicting MCT-mediated lactate exchanges between astrocytes and neurons in the brain. In the model, astrocytes, depicted on the left, have a high glycolytic metabolism. They import glucose via glucose transporters (GLUT) and then sequentially convert glucose to pyruvate and ATP using glycolysis, and pyruvate to lactate using lactate dehydrogenase A (LDHA). Lactate is exported together with protons via MCT4. Neurons, depicted on the right, import lactate and protons via MCT2. Lactate is oxidized to pyruvate by lactate dehydrogenase B (LDHB) and pyruvate fuels the TCA cycle to support ATP production through oxidative phosphorylation.

Fig. 2

Model depicting a metabolic symbiosis based on the exchange of lactate between glycolytic and oxidative cancer cells. In the model, glycolytic cancer cells, depicted on the left, import glucose via glucose transporters (GLUT) and then sequentially convert glucose to pyruvate and ATP using glycolysis, and pyruvate to lactate using lactate dehydrogenase A (LDHA). Lactate is exported together with protons via MCT4. Oxidative cancer cells, depicted on the right, import lactate and protons via MCT1. Lactate is oxidized to pyruvate by lactate dehydrogenase B (LDHB) generating NADH as a byproduct, and both pyruvate and NADH fuel the TCA cycle to support ATP production through oxidative phosphorylation.

Fig. 3

Model depicting proangiogenic lactate signaling in cancer. In the model, glycolytic cancer cells, depicted on the left, import glucose via glucose transporters (GLUT) and then sequentially convert glucose to pyruvate and ATP using glycolysis, and pyruvate to lactate using lactate dehydrogenase A (LDHA). Lactate is exported together with protons via MCT4. MCT1 is expressed in endothelial cells and in oxidative cancer cells, depicted on the left, and catalyzes the uptake of lactate together with protons. In these cells, lactate is oxidized to pyruvate by LDHB, producing NADH as a byproduct. Pyruvate inhibits prolylhydroxylases (PHDs). In endothelial cells, PHD inhibition stabilizes hypoxia-inducible factor (HIF-1) subunit α, triggering HIF-1 activation and the transcriptional upregulation of vascular endothelial growth factor receptor 2 (VEGFR2). HIF-1 also indirectly increases bFGF, which is secreted and activates the proangiogenic bFGF receptor (bFGFR). PHD inhibition further stabilizes inhibitor of NF-κB kinase β (Iκκβ), an inhibitor of inhibitor of NF-kB α (IκBα). NADH aliments NAD(P)H oxidases (Nox) that produce reactive oxygen species (ROS) to further inhibit IκBα. Consequently, transcription factor NF-κB is activated and upregulates IL-8, which is secreted and activates the proangiogenic IL-8 receptor (IL-8R). Oxidative cancer cells share with endothelial cells the lactate-HIF-1 pathway, but not the lactate-NF-κB pathway. HIF-1 activation by lactate in these cells transcriptionally upregulates VEGF, which upon secretion can activate proangiogenic VEGFR2 in endothelial cells. Lactate signaling as a whole can thus trigger angiogenesis independently of hypoxia.

Fig. 4

Model depicting metabolic commensalism of oxidative cancer cells for stromal cells. In the model, oxidative cancer cells, depicted on the right, produce reactive oxygen species (ROS) that promote glycolysis and MCT4 expression in stromal cells. Glycolytic stromal cells, depicted on the left, import glucose via glucose transporters (GLUT) and then sequentially convert glucose to pyruvate and ATP using glycolysis, and pyruvate to lactate using lactate dehydrogenase A (LDHA). They also produce ketone bodies. Lactate and ketone bodies are exported together with protons via MCT4. Oxidative cancer cells import lactate, ketone bodies and protons via MCT1. Lactate is oxidized to pyruvate by lactate dehydrogenase B (LDHB) generating NADH as a byproduct, and both pyruvate and NADH fuel the TCA cycle to support ATP production through oxidative phosphorylation. Ketone bodies can also be catabolized.

Fig. 5

Model showing the immunosuppressive activity of lactic acid on T cells. In the model, glycolytic cells, depicted on the left, import glucose via glucose transporters (GLUT) and then sequentially convert glucose to pyruvate and ATP using glycolysis, and pyruvate to lactate using lactate dehydrogenase A (LDHA). Lactate is exported together with protons via MCT4. Activated T lymphocytes, depicted on the right, also depend on a glycolytic metabolism and must release lactate and protons, which in these cells is facilitated by MCT1. MCT1, however, is a passive transporter that is antagonized by the high microenvironmental levels of lactic acid that can be found in glycolytic tissues.