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Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

EMBO molecular medicine, 2022-12, Vol.14 (12), p.e15343-n/a [Peer Reviewed Journal]

2022 The Authors. Published under the terms of the CC BY 4.0 license. ;2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License. ;Distributed under a Creative Commons Attribution 4.0 International License ;ISSN: 1757-4676 ;EISSN: 1757-4684 ;DOI: 10.15252/emmm.202115343 ;PMID: 36278433

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Title:
Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis
Author: Guyon, Joris ; Fernandez‐Moncada, Ignacio ; Larrieu, Claire M ; Bouchez, Cyrielle L ; Pagano Zottola, Antonio C ; Galvis, Johanna ; Chouleur, Tiffanie ; Burban, Audrey ; Joseph, Kevin ; Ravi, Vidhya M ; Espedal, Heidi ; Røsland, Gro Vatne ; Daher, Boutaina ; Barre, Aurélien ; Dartigues, Benjamin ; Karkar, Slim ; Rudewicz, Justine ; Romero‐Garmendia, Irati ; Klink, Barbara ; Grützmann, Konrad ; Derieppe, Marie‐Alix ; Molinié, Thibaut ; Obad, Nina ; Léon, Céline ; Seano, Giorgio ; Miletic, Hrvoje ; Heiland, Dieter Henrik ; Marsicano, Giovanni ; Nikolski, Macha ; Bjerkvig, Rolf ; Bikfalvi, Andreas ; Daubon, Thomas
Subjects: Angiogenesis ; Animals ; Antiepileptic agents ; antiepileptic drug ; Bioinformatics ; Brain cancer ; Brain Neoplasms - enzymology ; Brain Neoplasms - pathology ; Brain tumors ; Computer Science ; Dehydrogenases ; energy metabolism ; Gene amplification ; Glioblastoma ; Glioblastoma - enzymology ; Glioblastoma - pathology ; Hypoxia ; invasion ; Isoforms ; Lactate Dehydrogenases ; Lactic Acid ; Life Sciences ; Medical prognosis ; Metabolic networks ; Metabolism ; Metabolomics ; Mice ; Oxidative phosphorylation ; Phosphorylation ; Pyruvic acid ; Radiation ; Respiration ; Spheroids ; Stiripentol ; Survival ; Symbiosis ; Transcriptomics ; Tricarboxylic acid cycle ; Tumors
Is Part Of: EMBO molecular medicine, 2022-12, Vol.14 (12), p.e15343-n/a
Description: Lactate is a central metabolite in brain physiology but also contributes to tumor development. Glioblastoma (GB) is the most common and malignant primary brain tumor in adults, recognized by angiogenic and invasive growth, in addition to its altered metabolism. We show herein that lactate fuels GB anaplerosis by replenishing the tricarboxylic acid (TCA) cycle in absence of glucose. Lactate dehydrogenases (LDHA and LDHB), which we found spatially expressed in GB tissues, catalyze the interconversion of pyruvate and lactate. However, ablation of both LDH isoforms, but not only one, led to a reduction in tumor growth and an increase in mouse survival. Comparative transcriptomics and metabolomics revealed metabolic rewiring involving high oxidative phosphorylation (OXPHOS) in the LDHA/B KO group which sensitized tumors to cranial irradiation, thus improving mouse survival. When mice were treated with the antiepileptic drug stiripentol, which targets LDH activity, tumor growth decreased. Our findings unveil the complex metabolic network in which both LDHA and LDHB are integrated and show that the combined inhibition of LDHA and LDHB strongly sensitizes GB to therapy. Synopsis This study highlights the importance of metabolic symbiosis dependent on lactate and lactate dehydrogenase isoforms (LDHA and B) in glioblastoma development. Inhibiting both lactate dehydrogenases may be a novel potential therapeutic approach for targeting glioblastoma. Lactate, which is produced in hypoxic environments, is secreted and taken up by oxidative cells to fuel the Krebs cycle to promote growth and invasion. Only double knockout of LDHA/B abolished lactate production, reduced tumor growth and invasion, and prolonged mouse survival. Tumors that no longer express LDH become more oxidative and more sensitive to radiation. The use of the LDH inhibitor stiripentol in clinical practice may be therapeutically relevant for glioblastoma. This study highlights the importance of metabolic symbiosis dependent on lactate and lactate dehydrogenase isoforms (LDHA and B) in glioblastoma development. Targeting both lactate dehydrogenases may be a novel potential therapeutic approach for targeting glioblastoma.
Publisher: England: John Wiley & Sons, Inc
Language: English
Identifier: ISSN: 1757-4676
EISSN: 1757-4684
DOI: 10.15252/emmm.202115343
PMID: 36278433
Source: GFMER Free Medical Journals
MEDLINE
PubMed Central
ProQuest Central
DOAJ Directory of Open Access Journals

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Lactate dehydrogenases promote glioblastoma growth and invasion via a metabolic symbiosis

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