Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden – ScienceOpen
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      Targeted activation of Stat3 in combination with paclitaxel results in increased apoptosis in epithelial ovarian cancer cells and a reduced tumour burden

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          Abstract

          Objectives

          Stat3 is persistently activated in ovarian cancer cells, with a crucial role in tumour onset and progression. In this study, we examined the anti‐tumour effect of a small‐molecule inhibitor napabucasin (BBI608) on epithelial ovarian cancer (EOC) in vitro and in vivo, and investigated the underlying molecular mechanism of this drug in combination with paclitaxel.

          Materials and Methods

          A total of 156 ovarian cancer patient samples were analysed to determine the correlation between pStat3 expression in tumour cells and the prognosis of EOC patients. The anti‐tumour effect of BBI608 and/or paclitaxel on ovarian cancer in vitro was evaluated by CCK‐8, flow cytometry, Western blot and transwell assays. An in vivo intraperitoneal model was performed to confirm the effect of BBI608 on pStat3‐mediated peritoneal metastasis when combined with paclitaxel.

          Results

          Patients with high expression of pStat3 had poorer overall survival and progression‐free survival than those with low pStat3 expression. The synergy of BBI608 in combination with paclitaxel exerted dramatic growth inhibition and induced apoptosis in EOC cell lines. In vivo, the combination of two drugs significantly decreased intraperitoneal tumour burden and ascites volume, prolonged survival of tumour‐bearing mice compared with each monotherapy; these results were associated with downregulation of phospho‐Stat3 and activation of apoptosis pathway.

          Conclusions

          Targeting the activation of Stat3 may be a potential therapeutic approach for EOC by acting synergistically with paclitaxel.

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          Most cited references30

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          Newly diagnosed and relapsed epithelial ovarian carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

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            Stat3 mediates myeloid cell-dependent tumor angiogenesis in mice.

            The underlying molecular mechanisms that cause immune cells, mediators of our defense system, to promote tumor invasion and angiogenesis remain incompletely understood. Constitutively activated Stat3 in tumor cells has been shown to promote tumor invasion and angiogenesis. Therefore, we sought to determine whether Stat3 activation in tumor-associated inflammatory cells has a similar function. We found that Stat3 signaling mediates multidirectional crosstalk among tumor cells, myeloid cells in the tumor stroma, and ECs that contributes to tumor angiogenesis in mice. Myeloid-derived suppressor cells and macrophages isolated from mouse tumors displayed activated Stat3 and induced angiogenesis in an in vitro tube formation assay via Stat3 induction of angiogenic factors, including VEGF and bFGF. Stat3-regulated factors produced by both tumor cells and tumor-derived myeloid cells also induced constitutive activation of Stat3 in tumor endothelium, and inhibiting Stat3 in ECs substantially reduced in vitro tumor factor-induced endothelial migration and tube formation. In vivo assays demonstrated the requirement for Stat3 signaling in tumor-associated myeloid cells for tumor angiogenesis. Our results indicate that, by virtue of the ability of Stat3 in tumor cells and tumor-derived myeloid cells to upregulate expression of factors that activate Stat3 in ECs, Stat3 mediates multidirectional crosstalk among tumor cells, tumor-associated myeloid cells, and ECs that contributes to tumor angiogenesis.
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              Constitutive activation of Stat3 signaling confers resistance to apoptosis in human U266 myeloma cells.

              Interleukin 6 (IL-6) is the major survival factor for myeloma tumor cells and induces signaling through the STAT proteins. We report that one STAT family member, Stat3, is constitutively activated in bone marrow mononuclear cells from patients with multiple myeloma and in the IL-6-dependent human myeloma cell line U266. Moreover, U266 cells are inherently resistant to Fas-mediated apoptosis and express high levels of the antiapoptotic protein Bcl-xL. Blocking IL-6 receptor signaling from Janus kinases to the Stat3 protein inhibits Bcl-xL expression and induces apoptosis, demonstrating that Stat3 signaling is essential for the survival of myeloma tumor cells. These findings provide evidence that constitutively activated Stat3 signaling contributes to the pathogenesis of multiple myeloma by preventing apoptosis.
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                Author and article information

                Contributors
                xiazhaoscu@126.com
                xiaweiwei@scu.edu.cn
                Journal
                Cell Prolif
                Cell Prolif
                10.1111/(ISSN)1365-2184
                CPR
                Cell Proliferation
                John Wiley and Sons Inc. (Hoboken )
                0960-7722
                1365-2184
                28 November 2019
                January 2020
                : 53
                : 1 ( doiID: 10.1111/cpr.v53.1 )
                : e12719
                Affiliations
                [ 1 ] Department of Gynecology and Obstetrics Development and Related Disease of Women and Children Key Laboratory of Sichuan Province Key Laboratory of Birth Defects and Related Diseases of Women and Children Ministry of Education West China Second Hospital Sichuan University Chengdu China
                [ 2 ] Lab of Aging Research and Nanotoxicology State Key Laboratory of Biotherapy West China Hospital Sichuan University and Collaborative Innovation Center Chengdu China
                Author notes
                [*] [* ] Correspondence

                Xia Zhao and Xiawei Wei, No. 1 Keyuan Street Road 4, Gaopeng Street, Chengdu, Sichuan Province, 610041, China.

                Emails: xiazhaoscu@ 123456126.com ; xiaweiwei@ 123456scu.edu.cn

                Author information
                https://orcid.org/0000-0001-6162-4931
                https://orcid.org/0000-0002-6513-6422
                Article
                CPR12719
                10.1111/cpr.12719
                6985655
                31778258
                d087fad0-91d0-4bd3-a200-3f87ab395cf5
                © 2019 The Authors. Cell Proliferation Published by John Wiley & Sons Ltd.

                This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

                History
                : 27 August 2019
                : 16 October 2019
                : 17 October 2019
                Page count
                Figures: 5, Tables: 1, Pages: 14, Words: 9294
                Funding
                Funded by: the Excellent Youth Foundation of Sichuan Scientific Committee Grant in China.
                Award ID: No. 2019JDJQ0008
                Funded by: National Major Scientific and Technological Special Project for “Significant New Drugs Development”
                Award ID: (No. 2018ZX09733001)
                Funded by: National Natural Science Foundation of China , open-funder-registry 10.13039/501100001809;
                Award ID: (No. 81602492)
                Funded by: National Key Research and Development Program of China
                Award ID: (No. 2016YFA0201402)
                Categories
                Original Article
                Original Articles
                Custom metadata
                2.0
                January 2020
                Converter:WILEY_ML3GV2_TO_JATSPMC version:5.7.5 mode:remove_FC converted:18.02.2020

                Cell biology
                apoptosis,epithelial ovarian cancer,napabucasin (bbi608),paclitaxel,stat3 inhibitor
                Cell biology
                apoptosis, epithelial ovarian cancer, napabucasin (bbi608), paclitaxel, stat3 inhibitor

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