Oncotarget

Research Papers:

Enhanced Orai1 and STIM1 expression as well as store operated Ca2+ entry in therapy resistant ovary carcinoma cells

Sebastian Schmidt _, Guoxing Liu, Guilai Liu, Wenting Yang, Sabina Honisch, Stavros Pantelakos, Christos Stournaras, Arnd Hönig and Florian Lang

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Oncotarget. 2014; 5:4799-4810. https://doi.org/10.18632/oncotarget.2035

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Abstract

Sebastian Schmidt1, Guoxing Liu1, Guilai Liu1, Wenting Yang1, Sabina Honisch1, Stavros Pantelakos1,2, Christos Stournaras1,2, Arnd Hönig3, Florian Lang1

1 Department of Physiology, University of Tübingen, D72076 Tübingen, Germany

2 University of Crete Medical School, Department of Biochemistry, Voutes, Heraklion, 71110, Greece

3 Department of Gynecology, University Hospital of Würzburg, D97080 Würzburg, Germany

Correspondence:

Florian Lang, email:

Keywords: Ca2+ release activated Ca2+ channel, SOCE, Akt, SH-6, 2-APB, apoptosis

Received: April 22, 2014 Accepted: May 28, 2014 Published: May 28, 2014

Abstract

Mechanisms underlying therapy resistance of tumor cells include protein kinase Akt. Putative Akt targets include store-operated Ca2+-entry (SOCE) accomplished by pore forming ion channel unit Orai1 and its regulator STIM1. We explored whether therapy resistant (A2780cis) differ from therapy sensitive (A2780) ovary carcinoma cells in Akt, Orai1, and STIM1 expression, Ca2+-signaling and cell survival following cisplatin (100µM) treatment. Transcript levels were quantified with RT-PCR, protein abundance with Western blotting, cytosolic Ca2+-activity ([Ca2+]i) with Fura-2-fluorescence, SOCE from increase of [Ca2+]i following Ca2+-readdition after Ca2+-store depletion, and apoptosis utilizing flow cytometry. Transcript levels of Orai1 and STIM1, protein expression of Orai1, STIM1, and phosphorylated Akt, as well as SOCE were significantly higher in A2780cis than A2780 cells. SOCE was decreased by Akt inhibitor III (SH-6, 10µM) in A2780cis but not A2780 cells and decreased in both cell lines by Orai1 inhibitor 2-aminoethoxydiphenyl borate (2-ABP, 50µM). Phosphatidylserine exposure and late apoptosis following cisplatin treatment were significantly lower in A2780cis than A2780 cells, a difference virtually abolished by SH-6 or 2-ABP. In conclusion, Orai1/STIM1 expression and function are increased in therapy resistant ovary carcinoma cells, a property at least in part due to enhanced Akt activity and contributing to therapy resistance in those cells.


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