Abstract
Abstract Development of resistance to platinum compounds significantly hinders successful ovarian cancer treatment. Understanding the molecular alterations in chemo-resistance is important for developing therapeutic strategies for reversal of resistance. Vacuolar-H + −ATPases (V-ATPases) are multi-subunit proton pumps that play key roles in regulating cytosolic/extracellular pH and drug tolerance in tumor cells. The present study begins to decipher the role of V-ATPase `a’ subunit isoforms (major pH sensing unit) in cisplatin resistance. For this, cisplatin resistant human ovarian cancer cell lines A2780 and TOV112D were generated in lab by stepwise increase in drug pressure. Comparative expression profiling revealed that V-ATPase `a` subunit levels correlated with cisplatin resistance and each of the a1,a2 and a3 isoforms were significantly up regulated in the resistant lines. Isoform-specific shRNAs were employed to selectively and stably reduce mRNA levels for VATPase ‘a’ subunit in cisplatin resistant cell lines and determine their effect on cisplatin/carboplatin sensitivity, DNA damage and apoptosis. V-ATPase a2 or a3 isoform knocked down resistant lines exhibited sensitization to cisplatin and carboplatin. In vitro effects showed increased DNA damage by forming platinum DNA adducts which led to higher levels of apoptosis. In conclusion, inhibition of V-ATPase `a` subunit expression by monoclonal antibodies or V-ATPase inhibitors could serve as a therapeutic strategy to overcome cisplatin resistance and has a potential as a combination therapy along with platinum drugs for treatment of chemo-resistant ovarian carcinoma. Citation Format: Arpita Kulshrestha, Gajendra K. Katara, Sahithi Pamarthy, Alice Gilman-Sachs, Kenneth D. Beaman. Vacuolar ATPase ‘a’ subunit mediates platinum resistance in ovarian cancer. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 3757. doi:10.1158/1538-7445.AM2014-3757
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