How Warburg-Associated Lactic Acidosis Rewires Cancer Cell Energy Metabolism to Resist Glucose Deprivation

Abstract

Lactic acidosis, a hallmark of solid tumour microenvironment, originates from lactate hyperproduction and its co-secretion with protons by cancer cells displaying the Warburg effect. Long considered a side effect of cancer metabolism, lactic acidosis is now known to play a major role in tumour physiology, aggressiveness and treatment efficiency. Growing evidence shows that it promotes cancer cell resistance to glucose deprivation, a common feature of tumours. Here we review the current understanding of how extracellular lactate and acidosis, acting as a combination of enzymatic inhibitors, signal, and nutrient, switch cancer cell metabolism from the Warburg effect to an oxidative metabolic phenotype, which allows cancer cells to withstand glucose deprivation, and makes lactic acidosis a promising anticancer target. We also discuss how the evidence about lactic acidosis' effect could be integrated in the understanding of the whole-tumour metabolism and what perspectives it opens up for future research.

Keywords: Warburg effect; glucose deprivation; lactic acidosis; metabolic symbiosis; tumour heterogeneity.

Figure 1

Lactic acidosis rewires energy metabolism and maintains cellular homeostasis. Lactic acidosis enhances the uptake of folate, long-chain fatty acids, glutamine, and lactate. It represses glucose import, glycolysis (by inhibiting HK and PFK, its rate-limiting enzymes) and lactic fermentation. It enhances lactate conversion to pyruvate, routing of pyruvate and glutamine towards the TCA cycle, ATP generation by OxPhos, and coenzyme reduction by IDH1 and the oxidative PPP. It also upregulates CA IX expression, which basifies intracellular pH. Abbreviations: ASCT2: Alanine, Serine, Cysteine Transporter 2; CA IX: carbonate anhydrase 1; GLUT1: glucose transporter 1; HK: hexokinase; IDH1: isocitrate dehydrogenase 1; MCT1: monocarboxylate transporter 1; OxPhos: oxidative phosphorylation; PFK1: phosphofructokinase 1; PPP: pentose phosphate pathway; TCA: tricarboxylic acid.

Figure 2

Lactic acidosis would contribute to a metabolic symbiosis between fermenting and oxidative cells within tumours. In this model, two populations coexist in tumours: fermenting cells in hypoxic regions, and oxidative cells in normoxic regions where lactic acidosis would exert its effect. Fermenting cells would consume the glucose spared by oxidative cells and generate the lactate fueling them, both being in a metabolic symbiosis. Lactic acidosis promotes the switch from a fermenting to an oxidative phenotype.