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

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          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.

          Abstract

          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.

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          Most cited references36

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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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            Targeting lactate metabolism for cancer therapeutics.

            Lactate, once considered a waste product of glycolysis, has emerged as a critical regulator of cancer development, maintenance, and metastasis. Indeed, tumor lactate levels correlate with increased metastasis, tumor recurrence, and poor outcome. Lactate mediates cancer cell intrinsic effects on metabolism and has additional non-tumor cell autonomous effects that drive tumorigenesis. Tumor cells can metabolize lactate as an energy source and shuttle lactate to neighboring cancer cells, adjacent stroma, and vascular endothelial cells, which induces metabolic reprogramming. Lactate also plays roles in promoting tumor inflammation and in functioning as a signaling molecule that stimulates tumor angiogenesis. Here we review the mechanisms of lactate production and transport and highlight emerging evidence indicating that targeting lactate metabolism is a promising approach for cancer therapeutics.
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              MYC/PGC-1α Balance Determines the Metabolic Phenotype and Plasticity of Pancreatic Cancer Stem Cells.

              The anti-diabetic drug metformin targets pancreatic cancer stem cells (CSCs), but not their differentiated progenies (non-CSCs), which may be related to distinct metabolic phenotypes. Here we conclusively demonstrate that while non-CSCs were highly glycolytic, CSCs were dependent on oxidative metabolism (OXPHOS) with very limited metabolic plasticity. Thus, mitochondrial inhibition, e.g., by metformin, translated into energy crisis and apoptosis. However, resistant CSC clones eventually emerged during treatment with metformin due to their intermediate glycolytic/respiratory phenotype. Mechanistically, suppression of MYC and subsequent increase of PGC-1α were identified as key determinants for the OXPHOS dependency of CSCs, which was abolished in resistant CSC clones. Intriguingly, no resistance was observed for the mitochondrial ROS inducer menadione and resistance could also be prevented/reversed for metformin by genetic/pharmacological inhibition of MYC. Thus, the specific metabolic features of pancreatic CSCs are amendable to therapeutic intervention and could provide the basis for developing more effective therapies to combat this lethal cancer.
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                Author and article information

                Contributors
                cyril.corbet@uclouvain.be
                olivier.feron@uclouvain.be
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                23 March 2018
                23 March 2018
                2018
                : 9
                : 1208
                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
                [2 ]Louvain Drug Research Institute, Biomedical Magnetic Resonance Research Group, Université catholique de Louvain, 73 Avenue Mounier, REMA 73.08, Brussels, B-1200 Belgium
                [3 ]ISNI 0000 0001 0668 7884, GRID grid.5596.f, CISTIM Leuven, , Center for Drug Design and Discovery (CD3) KU Leuven, ; Gaston Geenslaan 2, Heverlee, 3001 Belgium
                [4 ]ISNI 0000 0001 2294 713X, GRID grid.7942.8, Laboratory of Cell Physiology, Institute of Neuroscience, , Université catholique de Louvain, ; Brussels, B-1200 Belgium
                [5 ]ISNI 0000 0001 2155 0333, GRID grid.7645.0, Division of Zoology/Membrane Transport, FB Biologie, , TU Kaiserslautern, ; P.O. Box 3049, Kaiserslautern, D-67653 Germany
                [6 ]ISNI 0000 0001 2294 713X, GRID grid.7942.8, Institute of Condensed Matter and Nanosciences, MOST division, Place Louis Pasteur, , Université catholique de Louvain, ; Louvain-la-Neuve, B-1348 Belgium
                [7 ]Present Address: Department of Oncology, Laboratory of Angiogenesis and Vascular Metabolism, and Vesalius Research Center, VIB, Herestraat 49 box 912, B-3000 Leuven, Belgium
                [8 ]ISNI 0000 0001 0126 6191, GRID grid.412970.9, Present Address: Institute of Physiological Chemistry, , University of Veterinary Medicine Hannover, ; Bünteweg 17, Hannover, D-30559 Germany
                Author information
                http://orcid.org/0000-0001-5360-0286
                Article
                3525
                10.1038/s41467-018-03525-0
                5865202
                29572438
                63710f9b-7862-4538-8d42-05012805da17
                © The Author(s) 2018

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

                History
                : 25 May 2017
                : 20 February 2018
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