Influence of oxygen on the Warburg effect: do cancer cells produce lactate only from glucose?

Abstract

The common characteristics of many tumors is phenomenon termed the Warburg effect – the production of abundant amounts of lactate in the presence of sufficient oxygen. It is commonly accepted that lactate is synthesized from glucose; hence, the other term for this phenomenon is aerobic glycolysis. Hypoxia, frequently observed in solid tumors, results in an increased HIF 1 transcription factor activity, which stimulates lactate synthesis by activating the transcription of glucose transporters and glycolytic enzymes genes, while inhibiting mitochondrial pyruvate metabolism. However, under normoxic conditions, when the HIF-1 factor is inactive, the lactate is the product not only of glycolysis, but also of glutaminolysis. Both pathways are activated by the c-myc transcription factor. Glutaminolysis, the mitochondrial pathway involving Krebs cycle enzymes, provides energy to the cell and the pathway intermediates (L-glutamate, L-aspartate, acetyl CoA) are substrates for the synthesis of nucleic acids, proteins and lipids. Subsequently, the cytoplasmic oxaloacetate-malate-pyruvate-lactate axis provides redox cofactors - NADPH for lipid and DNA synthesis and for cellular antioxidant systems as well as NAD+ necessary for efficient glycolysis resulting in increased lactate synthesis from glucose at normoxia. Thus, oxygen as Krebs cycle activator enhances lactate synthesis as the end product of glutaminolysis as well as promotes glycolytic lactate synthesis. In conclusion, the Warburg effect is the result of oxygen-induced extensive lactate production in both glycolysis and glutaminolysis pathways. Thus, an increased lactate synthesis at normoxia is just not the result of the cellular shift to extramitochondrial metabolism, but a manifestation of transcriptionally regulated adaptive response, allowing the cancer cells to acquire the energy and nutrients necessary for growth and proliferation.