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Siltuximab对卵巢癌中IL-6诱导的信号通路的影响
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Effects of siltuximab on the IL-6-induced signaling pathway in ovarian cancer |
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Guo Y, Nemeth J, O'Brien C, Susa M, Liu X, Zhang Z, Choy E, Mankin H, Hornicek F, Duan Z 2011/1/7 16:45:00 |
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Clinical Cancer Research, 2010, Volume 16, Issue 23
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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. ©2010 AACR.
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Correspondence Address: Duan, Z.; Sarcoma Biology Laboratory, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Boston, MA, United States; email:zduan@partners.org |
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