Up-regulated aerobic glycolysis is a hallmark of malignant cancers. Little is understood about the reasons why
malignant tumors up-regulate glycolysis and acidify their microenvironment. Signaling pathways involved in glucose
changes are numerous. However, the identity of the internal glucose signal remains obscure. In this review we address the
question of the significance of vacuolar proton ATPase (V-ATPase) and its relationship to up-regulated glycolysis in tumors.
We know that glycolysis is extremely sensitive to changes in pH. Importantly, the V-ATPase activity is sensitive to
glucose availability. Therefore, we propose that pH acts as the glucose signal via the V-ATPase that responds to changes
in intracellular pH and acts as a sensor. We hypothesize that the increase in glycolysis leads to intracellular acidification
and activates the V-ATPase to maintain a more alkaline intracellular pH in tumors by up-regulating glycolysis. This review
attempts to provide a comprehensive description of the current knowledge about the role of V-ATPase in cancer,
highlighting its role as a key player in the pH signaling pathway.
Keywords: V-ATPase, glycolysis, (Pro)Renin Receptor/ATP6ap2, Wnt/β-catenin, hypoxia-inducible factor, metastasis, glycolysis, mitochondria, microenvironment pH, plasmalemmal V-ATPase, embranes
Rights & PermissionsPrintExport