Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Review
. 2018 Aug;7(8):3800-3811.
doi: 10.1002/cam4.1594. Epub 2018 Jun 21.

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

Bradleigh Whitton  1   2 , Haruko Okamoto  2 , Graham Packham  1 , Simon J Crabb  1
Affiliations
Review

Vacuolar ATPase as a potential therapeutic target and mediator of treatment resistance in cancer

Bradleigh Whitton et al. Cancer Med. 2018 Aug.

Abstract

Vacuolar ATPase (V-ATPase) is an ATP-dependent H+ -transporter that pumps protons across intracellular and plasma membranes. It consists of a large multi-subunit protein complex and influences a wide range of cellular processes. This review focuses on emerging evidence for the roles for V-ATPase in cancer. This includes how V-ATPase dysregulation contributes to cancer growth, metastasis, invasion and proliferation, and the potential link between V-ATPase and the development of drug resistance.

Keywords: V-ATPase; cancer; drug resistance; invasion; metastasis; novel therapy.

PubMed Disclaimer

Figures

Figure 1
Figure 1
V‐ATPase structure. The V1 domain contains the A3B3 catalytic hexamer, the peripheral stalk made up of subunits E, G, C, and H, and D and F of the central rotor. ATP hydrolysis occurs in the A3B3 catalytic hexamer and the energy generated is used to drive the rotary mechanism. The Vo domain is integrated into the membrane and is responsible for proton translocation; it consists of subunits a, d, e and the proteolipid ring made up of c and c″. Many of the subunits are expressed in the form of multiple isoforms; the tissue enriched localization of some of the important isoforms is shown
Figure 2
Figure 2
V‐ATPase function. A, Intracellular V‐ATPase regulates multiple intracellular processes. In secretory vesicles, V‐ATPase generates a proton gradient that is used to drive the H+‐dependent uptake of neurotransmitters. In endosomes, low pH promotes the dissociation of ligands, such as low density lipoproteins, from their receptors, facilitating receptor recycling to the plasma membrane. In signaling endosomes, V‐ATPase promotes signaling to β‐catenin downstream of Wnt receptors, and can promote NOTCH signaling via enhanced cleavage to generate NICD. In the Golgi, V‐ATPase promotes binding of hydrolases to the mannose‐6‐phosphate receptor which is important for their delivery to the lysosome. In lysosomes, low pH is required for optimal activity of acid‐dependent proteases, such as cathepsins. Lysosomal V‐ATPase also acts to coordinate activity of AMPK and mTORC1 to regulated cellular catabolism vs anabolism in response to shifting microenvironmental cues. Note the figure is designed to illustrate some key functions of V‐ATPase and is not intended to portray all of the diverse functions that have been ascribed to V‐ATPase. B, Plasma membrane functions of V‐ATPase in specialized cell types including renal intercalated cells, osteoclasts, and clear epididymal cells
See this image and copyright information in PMC

Similar articles

See all similar articles

Cited by

See all "Cited by" articles

References

    1. Stransky L, Cotter K, Forgac M. The function of V‐ATPases in cancer. Physiol Rev. 2016;96:1071‐1091. - PMC - PubMed
    1. Sun‐Wada G‐H, Wada Y. Role of vacuolar‐type proton ATPase in signal transduction. Biochim Biophys Acta. 2015;1847:1166‐1172. - PubMed
    1. Pamarthy S, Kulshrestha A, Katara GK, Beaman KD. The curious case of vacuolar ATPase: regulation of signaling pathways. Mol Cancer. 2018;17:41. - PMC - PubMed
    1. Vaccari T, Duchi S, Cortese K, Tacchetti C, Bilder D. The vacuolar ATPase is required for physiological as well as pathological activation of the Notch receptor. Development. 2010;137:1825‐1832. - PMC - PubMed
    1. Yan Y, Denef N, Schüpbach T. The vacuolar proton pump (V‐ATPase) is required for Notch signaling and endosomal trafficking in Drosophila. Dev Cell. 2009;17:387‐402. - PMC - PubMed

Publication types

MeSH terms

Substances

-