Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer

Yuqi Guo, Jeffrey Nemeth, Colin O'Brien, Michiro Susa, Xianzhe Liu, Zhan Zhang, Edwin Choy, Henry Mankin, Francis Hornicek, Zhenfeng Duan

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Abstract

Purpose: To explore potential therapeutic strategies for interrupting the interleukin-6 (IL-6) signaling pathway, we measured IL-6 expression in ovarian cancer tissues, and evaluated the effects of a monoclonal anti-IL-6 antibody; siltuximab (CNTO 328), on levels of IL-6-induced Stat3 phosphorylation, Stat3 nuclear translocation, and Stat3 downstream antiapoptotic genes. We then looked for enhancing paclitaxel sensitivity in multidrug-resistant ovarian cancer cell lines. Experimental Design: Expressions of IL-6 in ovarian cancer patient specimens were assessed by immunohistochemistry. Effects of siltuximab on IL-6-induced activation of Stat3 in an ovarian cancer cell line were determined by Western blot and real-time analysis of Stat3 nucleocytoplasmic translocation. Influence of combination of siltuximab and paclitaxel on tumor growth was evaluated in a xenograft mouse mode in vivo. Results: Metastatic and drug-resistant recurrent tumors have significantly higher IL-6 expression when compared with the matched primary tumors. Siltuximab specifically suppressed IL-6-induced Stat3 phosphorylation and Stat3 nuclear translocation. Treatment with siltuximab significantly decreased the levels of Stat3 downstream proteins such as MCL-1, Bcl-XL, and survivin. Treatment with siltuximab reduced expression of multiple IL-6-induced genes in these cell lines. Furthermore, siltuximab increased the cytotoxic effects of paclitaxel in a paclitaxel resistant ovarian cancer cell line in vitro, but combination therapy with siltuximab did not have a significant effect on paclitaxel resistant tumor growth in vivo. Conclusions: These results show that siltuximab effectively block the IL-6 signaling pathways and IL-6-induced gene expression. Blockage of IL-6 signaling may provide benefits for the treatment of ovarian cancer.

Original languageEnglish
Pages (from-to)5759-5769
Number of pages11
JournalClinical Cancer Research
Volume16
Issue number23
DOIs
Publication statusPublished - 2010 Dec 1

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ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Guo, Y., Nemeth, J., O'Brien, C., Susa, M., Liu, X., Zhang, Z., Choy, E., Mankin, H., Hornicek, F., & Duan, Z. (2010). Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer. Clinical Cancer Research, 16(23), 5759-5769. https://doi.org/10.1158/1078-0432.CCR-10-1095