Fig. 3.

Function of V-ATPases in cancer cell survival, migration and invasion.

Cancer cells upregulate a3 and a4, which target V-ATPases to the plasma membrane, where they transport protons extracellularly. An acidic extracellular pH causes protonation of cancer drugs (Drug⁺), which prevents their diffusion into the cell. Once in the cytosol, cancer drugs diffuse into acidic compartments, where they are retained upon protonation and prevented from reaching their intended targets. Plasma membrane V-ATPases also promote cancer cell survival by removing cytosolic acid produced from glycolysis. Plasma membrane V-ATPases may contribute to cell migration by creating regions of alkaline pH (↑pH_i), which promote actin polymerization and branching near the plasma membrane. Alternatively, acidic extracellular pH may contribute to force generation at the leading edge through calcium influx. Finally, plasma membrane V-ATPases are thought to contribute to invasion by activating secreted proteases, which function to cleave extracellular matrix (ECM) components and to activate other secreted proteases such as matrix metalloproteases.