V-ATPase in cancer: mechanistic insights and therapeutic potentials

Vacuolar-type H+-ATPase (V-ATPase) is a crucial proton pump that plays an essential role in maintaining intracellular pH homeostasis and a variety of physiological processes. This review provides an in-depth exploration of the structural components, functional mechanisms, and regulatory modes of V-ATPase in cancer cells. Comprising two main domains, V₁ and V₀, V-ATPase drives the proton pump through ATP hydrolysis, sustaining the pH balance within the cell and organelles. In cancer cells, the enhanced activity of V-ATPase is closely associated with the proliferation and metastasis of tumor cells, and it promotes the growth and invasion of tumor cells by regulating pH values in the tumor microenvironment. Moreover, the interaction between V-ATPase and key metabolic regulatory factors, the mechanistic target of rapamycin complex 1 (mTORC1) and AMP-activated protein kinase (AMPK), impacts the metabolic state of cancer cells. The role of V-ATPase in tumor drug resistance and its regulatory mechanism in non-canonical autophagy offer new perspectives and potential targets for cancer therapy. Future research directions will focus on the specific mechanisms of action of V-ATPase in the tumor microenvironment and how to translate its inhibitors into clinical applications, providing significant scientific evidence for the development of new therapeutic strategies.