Zdralevic 2018 J Biol Chem
|Ždralević M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking SM, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O'Brien T, Oefner PJ, Renner K, Pouysségur J, Kreutz M (2018) Double genetic disruption of lactate dehydrogenase A and B is required to ablate the 'Warburg effect' restricting tumor growth to oxidative metabolism. J Biol Chem [Epub ahead of print].|
Zdralevic M, Brand A, Di Ianni L, Dettmer K, Reinders J, Singer K, Peter K, Schnell A, Bruss C, Decking SM, Koehl G, Felipe-Abrio B, Durivault J, Bayer P, Evangelista M, O'Brien T, Oefner PJ, Renner K, Pouyssegur J, Kreutz M (2018) J Biol Chem
Abstract: Increased glucose consumption distinguishes cancer cells from normal cells and is known as the "Warburg effect" due to 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 the pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both LDHA and LDHB genes in two cancer cell lines (human colon adenocarcinoma and murine melanoma). Surprisingly neither LDHA nor LDHB knockout strongly reduced lactate secretion. In contrast, the 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 twofold reduction in proliferation rates in vitro and in vivo compared with their wild-type counterparts. Under hypoxia (1% oxygen), however, the LDHA/B suppression completely abolished in vitro growth, consistent with the reliance on OXPHOS. Interestingly, the activation of the respiratory capacity operated by the LDHA/B-DKO genetic block, as well as the resilient growth were not a consequence of a long-term adaptation. They could be reproduced pharmacologically by treating wild-type 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 demonstrated 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, Genetic disruption, Metabolic plasticity, OXPHOS, Tumor growth, glycolysis, Warburg effect, Cancer biology, Glucose metabolism, Glycolysis, Lactate dehydrogenase, LDHA, LDHB, Lactic acid, Pentose phosphate pathway (PPP), Tumor metabolism • Bioblast editor: Plangger M • O2k-Network Lab: AT Vienna Kozlov AV, DE Regensburg Renner-Sattler K
Labels: MiParea: Respiration, Genetic knockout;overexpression Pathology: Cancer
Organism: Human Tissue;cell: Endothelial;epithelial;mesothelial cell Preparation: Intact cells, Permeabilized cells
Coupling state: LEAK, OXPHOS, ET Pathway: N, NS, ROX HRR: Oxygraph-2k