Tumor associated vacuolar H+-
ATPases (V-
ATPases) are multi-subunit
proton pumps that acidify tumor microenvironment, thereby promoting
tumor invasion. Subunit 'a' of its V0 domain is the major pH sensing unit that additionally controls sub-cellular targeting of V-
ATPase and exists in four different
isoforms. Our study reports an elevated expression of the V-ATPase-V0a2
isoform in
ovarian cancer(OVCA) tissues and cell lines(A2780, SKOV-3 and TOV-112D). Among all V0'a'
isoforms, V0a2 exhibited abundant expression on OVCA cell surface while normal ovarian epithelia did not. Sub-cellular distribution of V-ATPase-V0a2 confirmed its localization on plasma-membrane, where it was also co-associated with
cortactin, an
F-actin stabilizing
protein at leading edges of
cancer cells. Additionally, V0a2 was also localized in early and late endosomal compartments that are sites for modulations of several signaling pathways in
cancer. Targeted inhibition of V-ATPase-V0a2 suppressed
matrix metalloproteinase activity(
MMP-9 &
MMP-2) in OVCA cells. In conclusion, V-ATPase-V0a2
isoform is abundantly expressed on ovarian
tumor cell surface in association with invasion assembly related
proteins and plays critical role in
tumor invasion by modulating the activity of matrix-degrading
proteases. This study highlights for the first time, the importance of V-ATPase-V0a2
isoform as a distinct
biomarker and possible therapeutic target for treatment of ovarian
carcinoma.