Impact of Na + /Ca 2+ Exchangers on Therapy Resistance of Ovary Carcinoma Cells

Abstract

Background/Aims: According to previous observations, enhanced store-operated Ca 2+ -entry (SOCE) accomplished by the pore forming ion channel unit Orai1 and its regulator STIM1 contribute to therapy resistance of ovary carcinoma cells. Ca 2+ signaling is further shaped by Ca 2+ extrusion through K + -independent (NCX) and/or K + -dependent (NCKX) Na + /Ca 2+ -exchangers. The present study thus explored whether therapy resistance is further paralleled by altered expression and/or function of Na + /Ca 2+ -exchangers. Methods: In therapy resistant (A2780cis) and therapy sensitive (A2780sens) ovary carcinoma cells transcript levels were estimated from RT-PCR, cytosolic Ca 2+ -activity ([Ca 2+ ] i ) from Fura-2-fluorescence, Na + /Ca 2+ -exchanger activity from the increase of [Ca 2+ ] i (Δ[Ca 2+ ] i ) and from whole cell current (I ca ) following abrupt replacement of Na + containing (130 mM) and Ca 2+ free extracellular perfusate by Na + free and Ca 2+ 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[Ca 2+ ] i as well as I ca were significantly higher in therapy resistant than in therapy sensitive ovary carcinoma cells. The Na + /Ca 2+ -exchanger inhibitor KB-R7943 (10 μM) significantly blunted Δ[Ca 2+ ] 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 + /Ca 2+ -exchanger activity may contribute to the therapy sensitivity of ovary carcinoma cells.