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

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.

Interleukin-6 receptor and its ligand interleukin-6 are opposite markers for survival and infiltration with mature myeloid cells in ovarian cancer

“…However, we envision that once tumors have an autocrine production of IL-6, and can provide IL-6 needed for growth, signaling, and immunosuppressive actions, the receptor might be lost, and tumors may become more resistant. 36,37 Our data corroborate this hypothesis, since tumor expression of IL-6 and IL-6R are not correlated.…”

USP11-dependent selective cIAP2 deubiquitylation and stabilization determine sensitivity to Smac mimetics

“…cIAP2 is also induced by IL-1β and cisplatin, leading to apoptosis resistance. 40,41 In addition to these observations, elevated cIAP2 expression in certain cell lines renders cells resistant to Smac mimetics, suggesting that cIAP2 is the decisive factor for protecting cancer cells from Smac mimetic-induced apoptosis. 22 In this study, we show that a USP11-dependent mechanism selectively and specifically regulates cIAP2 stability independent of cIAP1, which may explain the diverse responses of cancer cells to treatment with Smac mimetics, which are currently being tested in the clinic (Figure 7i).…”

Human Mesenchymal Stem Cells Promote Cancer Motility and Cytokine Secretion in vitro

“…IL-6, a multifunctional regulator of immune responses and hematopoiesis, influences the proliferation and invasion potential of head and neck cancer directly [Kanazawa et al, 2007]. A study conducted by Cohen et al [2012] showed platinum resistance of ovarian cancer cells mediated by IL-6. This resistance towards cisplatin was reversible by blocking IL-6.…”