Vacuolar ATPase 'a2' isoform exhibits distinct cell surface accumulation and modulates matrix metalloproteinase activity in ovarian cancer
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Arpita Kulshrestha1, Gajendra K. Katara1, Safaa Ibrahim1,2, Sahithi Pamarthy1, Mukesh K. Jaiswal1, Alice Gilman Sachs1, Kenneth D. Beaman1
1Department of Microbiology and Immunology, Rosalind Franklin University of Medicine and Science, North Chicago, IL, USA
2Department of Microbiology and Immunology, Faculty of Pharmacy, Cairo University, Egypt
Kenneth D. Beaman, e-mail: [email protected]
Keywords: Vacuolar ATPase, a2 isoform, ovarian cancer, invasion, cortactin, MMP
Received: September 19, 2014 Accepted: December 14, 2014 Published: January 21, 2015
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.
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