Journal of Molecular Medicine

, Volume 91, Issue 3, pp 357–368

Platinum-resistance in ovarian cancer cells is mediated by IL-6 secretion via the increased expression of its target cIAP-2

  • Sharon Cohen
  • Ilan Bruchim
  • Dror Graiver
  • Zoharia Evron
  • Varda Oron-Karni
  • Metsada Pasmanik-Chor
  • Ram Eitan
  • Joelle Bernheim
  • Hanoch Levavi
  • Ami Fishman
  • Eliezer Flescher
Original Article

Abstract

Ovarian carcinoma patients are initially responsive to platinum-based therapy, but eventually become refractory to treatment due to the development of platinum chemoresistance. Elevated levels of interleukin-6 (IL-6) in the sera and ascites of these patients predict poor clinical outcome. Our goal was to analyze the interaction between cisplatin and cisplatin-resistant ovarian cancer cells, and to identify means of circumventing platinum resistance. We studied ovarian carcinoma cell lines and cells drawn from ovarian carcinoma patients. Gene array analyses were performed on ovarian carcinoma cells upon treatment with cisplatin, and the results were validated by ELISA and Western blotting (WB). Cytotoxicity assays were performed on anti-IL-6 Ab-, IL-6-, and cellular inhibitor of apoptosis 2 (cIAP-2) siRNA-treated cells, following cisplatin addition. Our results revealed a highly significant increase in IL-6 and cIAP-2 mRNA and protein levels upon treatment with cisplatin. WB analysis of cisplatin-treated cells exhibited decreased cIAP-2 expression level following anti-IL-6 Ab addition. Furthermore, IL-6 by itself, significantly increased cIAP-2 levels in ovarian carcinoma cells. Finally, cytotoxicity assays showed sensitization to cisplatin following the addition of IL-6 and cIAP-2 inhibitors. In conclusion, cisplatin treatment of ovarian carcinoma cells upregulates IL-6 and cIAP-2 levels while their inhibition significantly sensitizes them to cisplatin. Here, we present cIAP-2 as a novel inducer of platinum resistance in ovarian carcinoma cells, and suggest an axis beginning with an encounter between cisplatin and these cells, mediated sequentially by IL-6 and cIAP-2, resulting in cisplatin resistance. Consequently, we propose that combining IL-6/cIAP-2 inhibitors with cisplatin will provide new hope for ovarian carcinoma patients by improving the current treatment.

Keywords

Ovarian carcinoma Platinum resistance Cisplatin IL-6 cIAP-2 

Supplementary material

109_2012_946_MOESM1_ESM.doc (47 kb)
ESM 1DOC 47 kb

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Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Sharon Cohen
    • 1
  • Ilan Bruchim
    • 2
    • 3
  • Dror Graiver
    • 1
  • Zoharia Evron
    • 1
  • Varda Oron-Karni
    • 4
  • Metsada Pasmanik-Chor
    • 4
  • Ram Eitan
    • 5
    • 3
  • Joelle Bernheim
    • 6
    • 3
  • Hanoch Levavi
    • 5
    • 3
  • Ami Fishman
    • 2
    • 3
  • Eliezer Flescher
    • 1
  1. 1.Department of Clinical Microbiology and Immunology, Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  2. 2.Gynecology Oncology UnitMeir Medical CenterKfar SabaIsrael
  3. 3.Sackler School of MedicineTel Aviv UniversityTel AvivIsrael
  4. 4.Bioinformatics Unit, George S. Wise Faculty of Life SciencesTel Aviv UniversityTel AvivIsrael
  5. 5.Gynecology-Oncology UnitRabin Medical CenterPetah TikvaIsrael
  6. 6.Department of PathologyMeir Medical CenterKfar SabaIsrael

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