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In tumor cells, dysregulated pH gradient across cell membranes is a key physiological mechanism of metastasis\/chemo\u2010resistance. These pH alterations are mediated by aberrant activation of key multi\u2010subunit proton pumps, Vacuolar\u2010ATPases (V\u2010ATPases). In tumor cells, its \u2018a2\u2019 isoform (V\u2010ATPase\u2010V0a2) is a component of functional plasma\u2013membrane complex and promotes tumor invasion through tumor\u2010acidification and immuno\u2010modulation. Its involvement in chemo\u2010resistance has not been studied. Here, we show that V\u2010ATPase\u2010V0a2 is over\u2010expressed in acquired\u2010cisplatin resistant OVCA cells (cis\u2010A2780\/cis\u2010TOV112D). Of all the \u2018a\u2019 subunit isoforms, V\u2010ATPase\u2010V0a2 exhibited an elevated expression on plasma membrane of cisplatin\u2010resistant cells compared to sensitive counterparts. Immuno\u2010histochemistry revealed V\u2010ATPase\u2010V0a2 expression in both low grade (highly drug\u2010resistant) and high grade (highly recurrent) human OVCA tissues indicating its role in a centralized mechanism of tumor resistance. In cisplatin resistant cells, shRNA mediated inhibition of V\u2010ATPase\u2010V0a2 enhanced sensitivity towards both cisplatin and carboplatin. This improved cytotoxicity was mediated by enhanced cisplatin\u2010DNA\u2010adduct formation and suppressed DNA\u2010repair pathway, leading to enhanced apoptosis. Suppression of V0a2 activity strongly reduced cytosolic pH in resistant tumor cells, which is known to enhance platinum\u2010associated DNA\u2010damage. As an indicator of reduced metastasis and chemo\u2010resistance, in contrast to plasma membrane localization, a diffused cytoplasmic localization of acidic vacuoles was observed in V0a2\u2010knockdown resistant cells. Interestingly, pre\u2010treatment with monoclonal V0a2\u2010inhibitory antibody enhanced cisplatin cytotoxicity in resistant cells. Taken together, our findings suggest that the isoform specific inhibition of V\u2010ATPase\u2010V0a2 could serve as a therapeutic strategy for chemo\u2010resistant ovarian carcinoma and improve efficacy of platinum drugs.<\/jats:p>","DOI":"10.1016\/j.molonc.2016.01.003","type":"journal-article","created":{"date-parts":[[2016,1,29]],"date-time":"2016-01-29T10:21:26Z","timestamp":1454062886000},"page":"789-805","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":35,"title":["Selective inhibition of tumor cell associated Vacuolar\u2010ATPase \u2018a2\u2019 isoform overcomes cisplatin resistance in ovarian cancer cells"],"prefix":"10.1002","volume":"10","author":[{"given":"Arpita","family":"Kulshrestha","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gajendra K.","family":"Katara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jordyn","family":"Ginter","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sahithi","family":"Pamarthy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Safaa A.","family":"Ibrahim","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mukesh K.","family":"Jaiswal","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corina","family":"Sandulescu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ramayee","family":"Periakaruppan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James","family":"Dolan","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alice","family":"Gilman-Sachs","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenneth D.","family":"Beaman","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2016,1,29]]},"reference":[{"key":"e_1_2_8_2_1","doi-asserted-by":"publisher","DOI":"10.1038\/sj.onc.1207721"},{"key":"e_1_2_8_3_1","unstructured":"American Cancer Society Statistics for 2014. 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