Knockout of the a4 isoform of the V‐ATPase subunit a reduces tumor growth and metastasis in vivo

Abstract

The vacuolar ATPase (V‐ATPase) is an ATP‐dependent proton pump that transports protons across intracellular membranes and, in certain cell types including cancer cells, across the plasma membrane, where it promotes tumor survival and metastasis. V‐ATPase localization is regulated by different isoforms of subunit a, and it has been shown that the a3 and a4 isoforms both target V‐ATPases to the plasma membrane and are critical for migration and invasion of different cancer cell lines in vitro. By using CRISPR mediated gene editing to selectively disrupt each of the 4 isoforms (a1‐a4), we previously reported that the a4 isoform appears to be important for plasma membrane targeting of the V‐ATPase and migration and invasion of 4T1‐12B breast cancer cells in vitro. Using BALB/C mice as an animal model, we have investigated the effect of disruption of different isoforms of subunit a on tumor growth and metastasis in vivo. The results suggest that targeting plasma membrane V‐ATPases represents a novel therapeutic approach to inhibition of tumor growth and metastasis in breast cancer patients.