Impact of Na+/Ca2+ Exchangers on Therapy Resistance of Ovary Carcinoma Cells

Abstract

Background/Aims: According to previous observations, enhanced store-operated Ca²⁺-entry (SOCE) accomplished by the pore forming ion channel unit Orai1 and its regulator STIM1 contribute to therapy resistance of ovary carcinoma cells. Ca²⁺ signaling is further shaped by Ca²⁺ extrusion through K⁺-independent (NCX) and/or K⁺-dependent (NCKX) Na⁺/Ca²⁺-exchangers. The present study thus explored whether therapy resistance is further paralleled by altered expression and/or function of Na⁺/Ca²⁺-exchangers. Methods: In therapy resistant (A2780cis) and therapy sensitive (A2780sens) ovary carcinoma cells transcript levels were estimated from RT-PCR, cytosolic Ca²⁺-activity ([Ca²⁺]_i) from Fura-2-fluorescence, Na⁺/Ca²⁺-exchanger activity from the increase of [Ca²⁺]_i (Δ[Ca²⁺]_i) and from whole cell current (I_ca) following abrupt replacement of Na⁺ containing (130 mM) and Ca²⁺ free extracellular perfusate by Na⁺ free and Ca²⁺ containing (2 mM) extracellular perfusate, as well as cell death from PI -staining in flow cytometry. Results: The transcript levels of NCX3, NCKX4, NCKX5, and NCKX6, slope and peak of Δ[Ca²⁺]_i as well as I_ca were significantly higher in therapy resistant than in therapy sensitive ovary carcinoma cells. The Na⁺/Ca²⁺-exchanger inhibitor KB-R7943 (10 µM) significantly blunted Δ[Ca²⁺]_i and significantly augmented the cisplatin-induced cell death of therapy resistant ovary carcinoma cells without significantly modifying cisplatin-induced cell death of therapy sensitive ovary carcinoma cells. Conclusion: Enhanced Na⁺/Ca²⁺-exchanger activity may contribute to the therapy sensitivity of ovary carcinoma cells.