Item type: | Article | ||||||
---|---|---|---|---|---|---|---|
Journal or Publication Title: | J. Biol. Chem. | ||||||
Publisher: | AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC | ||||||
Place of Publication: | BETHESDA | ||||||
Volume: | 293 | ||||||
Number of Issue or Book Chapter: | 41 | ||||||
Page Range: | pp. 15947-15961 | ||||||
Date: | 12 October 2018 | ||||||
Institutions: | Medicine > Lehrstuhl für Chirurgie Medicine > Institut für Funktionelle Genomik > Lehrstuhl für Funktionelle Genomik (Prof. Oefner) Medicine > Lehrstuhl für Innere Medizin III (Hämatologie und Internistische Onkologie) Leibniz Institute for Immunotherapy (LIT) | ||||||
Identification Number: |
| ||||||
Keywords: | HYPOXIA-INDUCIBLE FACTORS; LACTIC-ACID; CELL-PROLIFERATION; AEROBIC GLYCOLYSIS; GLUCOSE-METABOLISM; CANCER-THERAPY; BREAST-CANCER; INHIBITION; EXPRESSION; SPECIFICITY; Warburg effect; glycolysis; glucose metabolism; pentose phosphate pathway (PPP); lactic acid; cancer biology; tumor metabolism; CRISPR; Cas; genetic disruption; lactate dehydrogenase; LDHA; LDHB; metabolic plasticity; OXPHOS; tumor growth | ||||||
Dewey Decimal Classification: | 600 Technology > 610 Medical sciences Medicine | ||||||
Status: | Published | ||||||
Refereed: | Yes, this version has been refereed | ||||||
Created at the University of Regensburg: | Partially | ||||||
Item ID: | 37895 |

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 ...

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.
Metadata last modified: 05 Nov 2018 14:49