Fig. 2

Link between proton dynamics and cancer metabolism. The cartoon represents glycolytic and oxidative cancer cells that can coexist in various types of cancers. Glycolytic cancer cells are well equipped for proton export. Passive transporters comprise monocarboxylate transporters (MCTs) among which MCT4 is well adapted for proton export, the sodium-proton exchanger NHE1, and the carbonic anhydrase IX (CA-IX)-sodium-bicarbonate exchanger (NBC) system that controls a cycle using bicarbonate to export protons. For intracellular ionic homeostasis, the NaK-ATPase exports sodium against potassium. In addition, proton pump V-ATPase can export protons when expressed at the plasma membrane. Of note, MCTs convey not only protons but also lactate, which is at the base of a metabolic relationship between glycolytic cancer cells that export lactate via MCT4 and oxidative cancer cells that import lactate primarily via MCT1 and use lactate to fuel OXPHOS and for intracellular signaling. Proton export and lactate exchange promote tumor growth, progression and dissemination, which constitutes the rationale for the preclinical and clinical evaluation of the various inhibitors represented in red. Figure adapted from [2]