Double genetic disruption of lactate dehydrogenases A and B is required to ablate the “Warburg effect” restricting tumor growth to oxidative metabolism
Abstract
Elevated glucose consumption distinguishes cancer cells from normal cells and is called the “Warburg effect” due to elevated glycolysis. Lactate dehydrogenase A (LDHA) is really a key glycolytic enzyme, a hallmark of aggressive cancers, and thought to be the main enzyme accountable for pyruvate-to-lactate conversion. To elucidate its role in tumor growth, we disrupted both LDHA and LDHB genes in 2 cancer cell lines (human colon adenocarcinoma and murine melanoma cells). Surprisingly, neither LDHA nor LDHB knockout strongly reduced lactate secretion. In comparison, double knockout (LDHA/B-DKO) fully covered up LDH activity and lactate secretion. In addition, under normoxia, LDHA/B-DKO cells survived the genetic block by shifting their metabolic process to oxidative phosphorylation (OXPHOS), entailing a couple-fold decrease in proliferation rates in vitro as well as in vivo in contrast to their WT counterparts. Under hypoxia (1% oxygen), however, LDHA/B suppression completely abolished in vitro growth, in conjuction with the reliance upon OXPHOS. Interestingly, activation from the respiratory system capacity run by the LDHA/B-DKO genetic block along with the resilient growth weren’t effects of lengthy-term adaptation. They may be reproduced pharmacologically by treating WT cells by having an LDHA/B-specific inhibitor (GNE-140). These bits of information show the Warburg effect isn’t just according to high LDHA expression, as both LDHA and LDHB have to be deleted to suppress fermentative glycolysis. Finally, we show the Warburg effect is dispensable even just in aggressive tumors which the metabolic shift to OXPHOS brought on by LDHA/B genetic disruptions accounts for the tumors’ escape and GNE-140 growth.