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To explore potential therapeutic strategies for interrupting the 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
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.
Metastatic and drug-resistant recurrent tumors have significantly higher IL-6 expression when compared to 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.
These results demonstrated 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.
Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital and Harvard Medical School.
This article was published in the following journal.
Name: Clinical cancer research : an official journal of the American Association for Cancer Research
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A complex signaling pathway whose name is derived from the DROSOPHILA Wg gene, which when mutated results in the wingless phenotype, and the vertebrate INT gene, which is located near integration sites of MOUSE MAMMARY TUMOR VIRUS. The signaling pathway is initiated by the binding of WNT PROTEINS to cells surface WNT RECEPTORS which interact with the AXIN SIGNALING COMPLEX and an array of second messengers that influence the actions of BETA CATENIN.
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A Wnt protein and ligand for FRIZZLED RECEPTORS that may function as an inhibitor or activator of the WNT SIGNALING PATHWAY. For example, it activates signaling in the presence of Frizzled-4 but is inhibitory when coupled with ROR2 TYROSINE KINASE. It is required for axis formation during EMBRYOGENESIS and inhibits the proliferation, migration, and invasiveness of cancer cells.
A sub-family of smad proteins that inhibit cell signaling by RECEPTOR-REGULATED SMAD PROTEINS. They form autoinhibitory feedback loops in the TGF-BETA signaling pathway and mediate signaling cross-talk with other signaling pathways
A family of intracellular tyrosine kinases that participate in the signaling cascade of cytokines by associating with specific CYTOKINE RECEPTORS. They act upon STAT TRANSCRIPTION FACTORS in signaling pathway referred to as the JAK/STAT pathway. The name Janus kinase refers to the fact the proteins have two phosphate-transferring domains.
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