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      The Regulation and Function of Lactate Dehydrogenase A: Therapeutic Potential in Brain Tumor

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          Abstract

          There are over 120 types of brain tumor and approximately 45% of primary brain tumors are gliomas, of which glioblastoma multiforme ( GBM) is the most common and aggressive with a median survival rate of 14 months. Despite progress in our knowledge, current therapies are unable to effectively combat primary brain tumors and patient survival remains poor. Tumor metabolism is important to consider in therapeutic approaches and is the focus of numerous research investigations. Lactate dehydrogenase A ( LDHA) is a cytosolic enzyme, predominantly involved in anaerobic and aerobic glycolysis (the Warburg effect); however, it has multiple additional functions in non‐neoplastic and neoplastic tissues, which are not commonly known or discussed. This review summarizes what is currently known about the function of LDHA and identifies areas that would benefit from further exploration. The current knowledge of the role of LDHA in the brain and its potential as a therapeutic target for brain tumors will also be highlighted. The Warburg effect appears to be universal in tumors, including primary brain tumors, and LDHA (because of its involvement with this process) has been identified as a potential therapeutic target. Currently, there are, however, no suitable LDHA inhibitors available for tumor therapies in the clinic.

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          Most cited references153

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          Understanding the Warburg effect: the metabolic requirements of cell proliferation.

          In contrast to normal differentiated cells, which rely primarily on mitochondrial oxidative phosphorylation to generate the energy needed for cellular processes, most cancer cells instead rely on aerobic glycolysis, a phenomenon termed "the Warburg effect." Aerobic glycolysis is an inefficient way to generate adenosine 5'-triphosphate (ATP), however, and the advantage it confers to cancer cells has been unclear. Here we propose that the metabolism of cancer cells, and indeed all proliferating cells, is adapted to facilitate the uptake and incorporation of nutrients into the biomass (e.g., nucleotides, amino acids, and lipids) needed to produce a new cell. Supporting this idea are recent studies showing that (i) several signaling pathways implicated in cell proliferation also regulate metabolic pathways that incorporate nutrients into biomass; and that (ii) certain cancer-associated mutations enable cancer cells to acquire and metabolize nutrients in a manner conducive to proliferation rather than efficient ATP production. A better understanding of the mechanistic links between cellular metabolism and growth control may ultimately lead to better treatments for human cancer.
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            Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1.

            The pyruvate kinase isoforms PKM1 and PKM2 are alternatively spliced products of the PKM2 gene. PKM2, but not PKM1, alters glucose metabolism in cancer cells and contributes to tumorigenesis by mechanisms that are not explained by its known biochemical activity. We show that PKM2 gene transcription is activated by hypoxia-inducible factor 1 (HIF-1). PKM2 interacts directly with the HIF-1α subunit and promotes transactivation of HIF-1 target genes by enhancing HIF-1 binding and p300 recruitment to hypoxia response elements, whereas PKM1 fails to regulate HIF-1 activity. Interaction of PKM2 with prolyl hydroxylase 3 (PHD3) enhances PKM2 binding to HIF-1α and PKM2 coactivator function. Mass spectrometry and anti-hydroxyproline antibody assays demonstrate PKM2 hydroxylation on proline-403/408. PHD3 knockdown inhibits PKM2 coactivator function, reduces glucose uptake and lactate production, and increases O(2) consumption in cancer cells. Thus, PKM2 participates in a positive feedback loop that promotes HIF-1 transactivation and reprograms glucose metabolism in cancer cells. Copyright © 2011 Elsevier Inc. All rights reserved.
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              Cutting edge: distinct glycolytic and lipid oxidative metabolic programs are essential for effector and regulatory CD4+ T cell subsets.

              Stimulated CD4(+) T lymphocytes can differentiate into effector T cell (Teff) or inducible regulatory T cell (Treg) subsets with specific immunological roles. We show that Teff and Treg require distinct metabolic programs to support these functions. Th1, Th2, and Th17 cells expressed high surface levels of the glucose transporter Glut1 and were highly glycolytic. Treg, in contrast, expressed low levels of Glut1 and had high lipid oxidation rates. Consistent with glycolysis and lipid oxidation promoting Teff and Treg, respectively, Teff were selectively increased in Glut1 transgenic mice and reliant on glucose metabolism, whereas Treg had activated AMP-activated protein kinase and were dependent on lipid oxidation. Importantly, AMP-activated protein kinase stimulation was sufficient to decrease Glut1 and increase Treg generation in an asthma model. These data demonstrate that CD4(+) T cell subsets require distinct metabolic programs that can be manipulated in vivo to control Treg and Teff development in inflammatory diseases.
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                Author and article information

                Journal
                Brain Pathol
                Brain Pathol
                10.1111/(ISSN)1750-3639
                BPA
                Brain Pathology
                John Wiley and Sons Inc. (Hoboken )
                1015-6305
                1750-3639
                17 September 2015
                January 2016
                : 26
                : 1 ( doiID: 10.1111/bpa.2016.26.issue-1 )
                : 3-17
                Affiliations
                [ 1 ] Cellular & Molecular Neuro‐oncology Research Group University of Portsmouth, School of Pharmacy & Biomedical Sciences Portsmouth UK
                Author notes
                [*] [* ] Corresponding author:

                Cara Valvona, BSc, Cellular & Molecular Neuro‐oncology Research Group, School of Pharmacy & Biomedical Sciences, University of Portsmouth, St Michael's Building, White Swan Road, Portsmouth PO1 2DT, UK (E‐mail: Cara.Valvona@ 123456port.ac.uk )

                Author information
                http://orcid.org/0000-0001-9108-3427
                Article
                BPA12299
                10.1111/bpa.12299
                8029296
                26269128
                0954e306-848e-4446-861b-2b0f55c1f068
                © 2015 The Authors. Brain Pathology published by John Wiley & Sons Ltd on behalf of International Society of Neuropathology.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 11 May 2015
                : 05 August 2015
                Page count
                Pages: 15
                Funding
                Funded by: Brain Tumour Research
                Funded by: Charlie's Challenge
                Funded by: Ali's Dream
                Categories
                Review
                Review
                Custom metadata
                2.0
                January 2016
                Converter:WILEY_ML3GV2_TO_JATSPMC version:6.0.1 mode:remove_FC converted:31.03.2021

                Pathology
                aerobic glycolysis,brain tumor,lactate,ldha,therapeutic target,tumor metabolism,warburg
                Pathology
                aerobic glycolysis, brain tumor, lactate, ldha, therapeutic target, tumor metabolism, warburg

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