Jacques Pouyssegur

Abstract

First, we will discuss how fermentative glycolysis, a primitive hypoxic imprinted metabolic pathway present at the Origin of life is instrumental for the rapid growth of cancers, regenerating tissues, immune cells but also bacteria and viruses during infections. The ‘Warburg effect’, activated via Myc and HIF-1 respectively in response to growth factors and hypoxia, is a Master metabolic and bioenergetic pathway which satisfies energetic demands required for rapid genome replication. 

Second, we will present the key role of lactic acid, the end-product of fermentative glycolysis able to move across cell membranes in both directions via two monocarboxylate transporters: ( MCT1, MCT4) contributing to cell-pH homeostasis but also to the complex immune response via acidosis of the tumour microenvironment. Importantly lactate is recycled in multiple organs as a major metabolic precursor of gluconeogenesis and energy source protecting cells and animals from harsh nutritional or oxygen restrictions. 

Third, we will revisit the Warburg effect via CRISPR-Cas9 disruption of glucose-6-phosphate isomerase (GPI-KO) or lactate dehydrogenases (LDHA/B-DKO) in two aggressive tumours (human melanoma B16-F10, colorectal adenocarcinoma LS174T). Full suppression of lactic acid production reduces but does not suppress tumour growth due to reactivation of OXPHOS. In contrast, disruption of the lactic acid transporters MCT1, MCT4 suppressed glycolysis, mTORC1, and tumour growth as a result of intracellular acidosis. 

Finally, we will briefly discuss the current clinical developments of an MCT1 specific drug AZ3965, and the recent progress for a specific in vivo MCT4 inhibitor, two drugs of very high potential for future clinical applications  against cancers, bacterial and viral pathogens.