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      Monocarboxylate transporters in cancer

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          Abstract

          Background

          Tumors are highly plastic metabolic entities composed of cancer and host cells that can adopt different metabolic phenotypes. For energy production, cancer cells may use 4 main fuels that are shuttled in 5 different metabolic pathways. Glucose fuels glycolysis that can be coupled to the tricarboxylic acid (TCA) cycle and oxidative phosphorylation (OXPHOS) in oxidative cancer cells or to lactic fermentation in proliferating and in hypoxic cancer cells. Lipids fuel lipolysis, glutamine fuels glutaminolysis, and lactate fuels the oxidative pathway of lactate, all of which are coupled to the TCA cycle and OXPHOS for energy production. This review focuses on the latter metabolic pathway.

          Scope of review

          Lactate, which is prominently produced by glycolytic cells in tumors, was only recently recognized as a major fuel for oxidative cancer cells and as a signaling agent. Its exchanges across membranes are gated by monocarboxylate transporters MCT1-4. This review summarizes the current knowledge about MCT structure, regulation and functions in cancer, with a specific focus on lactate metabolism, lactate-induced angiogenesis and MCT-dependent cancer metastasis. It also describes lactate signaling via cell surface lactate receptor GPR81.

          Major conclusions

          Lactate and MCTs, especially MCT1 and MCT4, are important contributors to tumor aggressiveness. Analyses of MCT-deficient (MCT +/- and MCT −/-) animals and (MCT-mutated) humans indicate that they are druggable, with MCT1 inhibitors being in advanced development phase and MCT4 inhibitors still in the discovery phase. Imaging lactate fluxes non-invasively using a lactate tracer for positron emission tomography would further help to identify responders to the treatments.

          Highlights

          • In cancer, hypoxia and cell proliferation are associated to lactic acid production.

          • Lactate exchanges are at the core of tumor metabolism.

          • Transmembrane lactate trafficking depends on monocarboxylate transporters (MCTs).

          • MCTs are implicated in tumor development and aggressiveness.

          • Targeting MCTs is a therapeutic option for cancer treatment.

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          Most cited references 212

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          LDHA-Associated Lactic Acid Production Blunts Tumor Immunosurveillance by T and NK Cells.

          Elevated lactate dehydrogenase A (LDHA) expression is associated with poor outcome in tumor patients. Here we show that LDHA-associated lactic acid accumulation in melanomas inhibits tumor surveillance by T and NK cells. In immunocompetent C57BL/6 mice, tumors with reduced lactic acid production (Ldha(low)) developed significantly slower than control tumors and showed increased infiltration with IFN-γ-producing T and NK cells. However, in Rag2(-/-)γc(-/-) mice, lacking lymphocytes and NK cells, and in Ifng(-/-) mice, Ldha(low) and control cells formed tumors at similar rates. Pathophysiological concentrations of lactic acid prevented upregulation of nuclear factor of activated T cells (NFAT) in T and NK cells, resulting in diminished IFN-γ production. Database analyses revealed negative correlations between LDHA expression and T cell activation markers in human melanoma patients. Our results demonstrate that lactic acid is a potent inhibitor of function and survival of T and NK cells leading to tumor immune escape.
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            Lactate Metabolism in Human Lung Tumors

            Cancer cells consume glucose and secrete lactate in culture. It is unknown whether lactate contributes to energy metabolism in living tumors. We previously reported that human non-small cell lung cancers (NSCLC) oxidize glucose in the tricarboxylic acid (TCA) cycle. Here we show that lactate is also a TCA cycle carbon source for NSCLC. In human NSCLC, evidence of lactate utilization was most apparent in tumors with high 18 fluorodeoxyglucose uptake and aggressive oncological behavior. Infusing human NSCLC patients with 13 C-lactate revealed extensive labeling of TCA cycle metabolites. In mice, deleting monocarboxylate transporter-1 (MCT1) from tumor cells eliminated lactate-dependent metabolite labeling, confirming tumor-cell autonomous lactate uptake. Strikingly, directly comparing lactate and glucose metabolism in vivo indicated that lactate's contribution to the TCA cycle predominates. The data indicate that tumors, including bona fide human NSCLC, can use lactate as a fuel in vivo. Human non-small cell lung cancer preferentially utilizes lactate over glucose to fuel TCA cycle and sustain tumor metabolism in vivo.
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              The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism.

              The monocarboxylate transporter MCT4 mediates lactic acid efflux from most tissues that are dependent on glycolysis for their ATP production. Here we demonstrate that expression of MCT4 mRNA and protein was increased >3-fold by a 48-h exposure to 1% O(2), whereas MCT1 expression was not increased. The effect was mimicked by CoCl(2) (50 microm), suggesting transcriptional regulation by hypoxia-inducible factor 1alpha (HIF-1alpha). The predicted promoters for human MCT1, MCT2, and MCT4 were cloned into the pGL3 vector and shown to be active (luciferase luminescence) under basal conditions. Only the MCT4 promoter was activated (>2-fold) by hypoxia. No response was found in cells lacking HIF-1alpha. Four potential hypoxia-response elements were identified, but deletion analysis implicated only two in the hypoxia response. These were just upstream from the transcription start site and also found in the mouse MCT4 promoter. Mutation of site 2 totally abolished the hypoxic response, whereas mutation of site 1 only reduced the response. Gel-shift analysis demonstrated that nuclear extracts of hypoxic but not normoxic HeLa cells contained two transcription factors that bound to DNA probes containing these hypoxia-response elements. The major shifted band was abolished by mutation of site 2, and supershift analysis confirmed that HIF-1alpha bound to this site. Binding of the second factor was abolished by mutation of site 1. We conclude that MCT4, like other glycolytic enzymes, is up-regulated by hypoxia through a HIF-1alpha-mediated mechanism. This adaptive response allows the increased lactic acid produced during hypoxia to be rapidly lost from the cell.
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                Author and article information

                Contributors
                Journal
                Mol Metab
                Mol Metab
                Molecular Metabolism
                Elsevier
                2212-8778
                27 July 2019
                March 2020
                27 July 2019
                : 33
                : 48-66
                Affiliations
                [1 ]Pole of Pharmacology & Therapeutics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
                [2 ]Pole of Pediatrics, Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain (UCLouvain), Brussels, Belgium
                [3 ]Louvain Drug Research Institute (LDRI), Université catholique de Louvain (UCLouvain), Brussels, Belgium
                [4 ]Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Torino, Torino, Italy
                Author notes
                []Corresponding author. Pole of Pharmacology & Therapeutics, Université catholique de Louvain (UCLouvain), Avenue Hippocrate 57 box B1.57.04, 1200 Brussels, Belgium. pierre.sonveaux@ 123456uclouvain.be
                Article
                S2212-8778(19)30403-X
                10.1016/j.molmet.2019.07.006
                7056923
                31395464
                3078d028-b97a-4c5d-bf0b-388f3de2bfd1
                © 2019 The Authors

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

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