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 (x0394;[Ca2+]i) and from whole cell current (Ica) 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 x0394;[Ca2+]i as well as Ica were significantly higher in therapy resistant than in therapy sensitive ovary carcinoma cells. The Na+/Ca2+-exchanger inhibitor KB-R7943 (10 µM) significantly blunted x0394;[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.

• Authors: Lisann Pelzl, Zohreh Hosseinzadeh, Kousi Alzoubi, Tamer Al-Maghout, Sebastian Schmidt, Christos Stournaras, Florian Lang
• Journal: Cellular physiology and biochemistry : international journal of experimental cellular physiology, biochemistry, and pharmacology (Cell Physiol Biochem) Vol. 37 Issue 5 Pg. 1857-68 ( 2015) ISSN: 1421-9778 [Electronic] Germany
• PMID: 26584285 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: © 2015 The Author(s) Published by S. Karger AG, Basel.

Chemical References

• 2-(2-(4-(4-nitrobenzyloxy)phenyl)ethyl)isothiourea methanesulfonate
• Ions
• Protein Isoforms
• Sodium-Calcium Exchanger
• Thiourea
• Cisplatin
• Calcium
• Fura-2

Topics

• Apoptosis (drug effects)
• Calcium (metabolism)
• Cell Line, Tumor
• Cisplatin (pharmacology, therapeutic use)
• Drug Resistance, Neoplasm (genetics)
• Female
• Fura-2 (chemistry)
• Humans
• Ions (chemistry, metabolism)
• Ovarian Neoplasms (drug therapy, metabolism, pathology)
• Patch-Clamp Techniques
• Protein Isoforms (antagonists & inhibitors, genetics, metabolism)
• Real-Time Polymerase Chain Reaction
• Sodium-Calcium Exchanger (antagonists & inhibitors, genetics, metabolism)
• Thiourea (analogs & derivatives, pharmacology, therapeutic use)