Fig.3.

Potentials sources of lactic acid production. A. Activated T-cells, such as those stimulated an anti-PD-1 antibody such as nivolumab, are known to have increased glycolysis, leading to lactic acid production via lactate dehydrogenase (LDH). Lactic acid is exported from the cell via a monocarboxylase transporter (MCT) B. Alternatively, in clear cell RCC cells, Von Hippel Lindau (VHL) mutated tumor cells lose their ability to degrade hypoxia induced factor (HIF). The accumulation of HIF promotes anaerobic glycolysis, which produces lactic acid as an end product. mTOR signaling enhances anaerobic glycolysis further, increasing the localization of glucose transporters (Glut1) to the cell membrane for more efficient glucose uptake. Everolimus, the mammalian target of rapamycin (mTOR) inhibitor, blocks HIF translation, promotes the degradation of HIF via the proteasome, and limits glucose importation from glucose transporters, culminating in decreased glycolysis.