2. Academic Validation
  3. Double genetic disruption of lactate dehydrogenases A and B is required to ablate the "Warburg effect" restricting tumor growth to oxidative metabolism

Double genetic disruption of lactate dehydrogenases A and B is required to ablate the "Warburg effect" restricting tumor growth to oxidative metabolism

  • J Biol Chem. 2018 Oct 12;293(41):15947-15961. doi: 10.1074/jbc.RA118.004180.
Maša Ždralević 1,  Almut Brand 1 2,  Lorenza Di Ianni 1,  Katja Dettmer 3,  Jörg Reinders 3,  Katrin Singer 2,  Katrin Peter 2 4,  Annette Schnell 2,  Christina Bruss 2,  Sonja-Maria Decking 2,  Gudrun Koehl 5,  Blanca Felipe-Abrio 1,  Jérôme Durivault 6,  Pascale Bayer 7,  Marie Evangelista 8,  Thomas O'Brien 8,  Peter J Oefner 3,  Kathrin Renner 2 4,  Jacques Pouysségur 9 6,  Marina Kreutz 10 4
Affiliations

Affiliations

  • 1 From the Université Côte d'Azur, IRCAN, CNRS, INSERM, Centre A. Lacassagne, 06189 Nice, France.
  • 2 the Departments of Internal Medicine III and.
  • 3 the Institute of Functional Genomics and.
  • 4 Center for Interventional Immunology, University of Regensburg, 93053 Regensburg, Germany.
  • 5 Surgery, University Hospital Regensburg, 93053 Regensburg, Germany.
  • 6 the Medical Biology Department, Centre Scientifique de Monaco, Monaco MC98000.
  • 7 the Université Côte d'Azur, University Hospital Pasteur, Clinical Chemistry Laboratory, 06001 Nice, France.
  • 8 Discovery and Translational Oncology, Genentech, South San Francisco, California 94080, and.
  • 9 From the Université Côte d'Azur, IRCAN, CNRS, INSERM, Centre A. Lacassagne, 06189 Nice, France, pouysseg@unice.fr.
  • 10 the Departments of Internal Medicine III and Marina.Kreutz@klinik.uni-regensburg.de.
PMID: 30158244 DOI: 10.1074/jbc.RA118.004180
Abstract

Increased glucose consumption distinguishes Cancer cells from normal cells and is known as the "Warburg effect" because of increased glycolysis. Lactate Dehydrogenase A (LDHA) is a key glycolytic Enzyme, a hallmark of aggressive cancers, and believed to be the major Enzyme responsible for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both the LDHA and LDHB genes in two Cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither LDHA nor LDHB knockout strongly reduced lactate secretion. In contrast, double knockout (LDHA/B-DKO) fully suppressed LDH activity and lactate secretion. Furthermore, under normoxia, LDHA/B-DKO cells survived the genetic block by shifting their metabolism to Oxidative Phosphorylation (OXPHOS), entailing a 2-fold reduction in proliferation rates in vitro and in vivo compared with their WT counterparts. Under hypoxia (1% oxygen), however, LDHA/B suppression completely abolished in vitro growth, consistent with the reliance on OXPHOS. Interestingly, activation of the respiratory capacity operated by the LDHA/B-DKO genetic block as well as the resilient growth were not consequences of long-term adaptation. They could be reproduced pharmacologically by treating WT cells with an LDHA/B-specific inhibitor (GNE-140). These findings demonstrate that the Warburg effect is not only based on high LDHA expression, as both LDHA and LDHB need to be deleted to suppress fermentative glycolysis. Finally, we demonstrate that the Warburg effect is dispensable even in aggressive tumors and that the metabolic shift to OXPHOS caused by LDHA/B genetic disruptions is responsible for the tumors' escape and growth.

Keywords

CRISPR/Cas; LDHA; LDHB; OXPHOS; Warburg effect; cancer biology; genetic disruption; glucose metabolism; glycolysis; lactate dehydrogenase; lactic acid; metabolic plasticity; pentose phosphate pathway (PPP); tumor growth; tumor metabolism.

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