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Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells

Oncogene volume 20, pages 7925–7934 (2001)Cite this article

Abstract

Signal transducers and activators of transcription (STATs) are transcription factors activated in response to cytokines and growth factors. Constitutively active Stat3 has been shown to mediate oncogenic transformation in cultured cells and induce tumor formation in mice. An increasing number of tumor-derived cell lines as well as samples from human cancer have been reported to express constitutively active Stat3 protein. We previously demonstrated that ovarian cancer cell lines express high levels of constitutively active Stat3. In this study, we show that inhibition of the Stat3 signaling pathway using the Janus Kinase-selective inhibitor, AG490, and a dominant negative Stat3 (Stat3β) significantly suppresses the growth of ovarian and breast cancer cell lines harboring constitutively active Stat3. In the ovarian cancer cell lines, AG490 also diminished the phosphorylation of Stat3, Stat3 DNA binding activity, and the expression of Bcl-xL. Further, AG490 induced significant apoptosis in ovarian and breast cancer cell lines expressing high levels of constitutively active Stat3 but had a less profound effect on normal cells lacking constitutively active Stat3. AG490 also enhanced apoptosis induced by cisplatin in ovarian cancer cells. These results suggest that inhibition of Stat3 signaling may provide a potential therapeutic approach for treating ovarian and breast cancers.

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Acknowledgements

We thank Stephen Ethier at the University of Michigan for providing the MCF-10A cells and Mats Ljungman at the University of Michigan for providing the normal human skin fibroblasts. We also thank Rupali Patel at the University of Michigan for technical assistance. We acknowledge Richard Jove at the H. Lee Moffitt Cancer Center for providing the Stat3β cDNA. This work was generously supported by a research grant from the Gustavus and Louise Pfeiffer Research Foundation.

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Author notes

  1. William M Burke and Xiaohong Jin: WM Burke and X Jin contributed equally to this work

Authors and Affiliations

  1. Division of Gynecologic Oncology, Department of Obstetrics and Gynecology, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109-0936, Michigan, USA

    William M Burke, Xiaohong Jin, Huey-Jen Lin, Melinda Huang, Rebecca Liu, R Kevin Reynolds & Jiayuh Lin

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  1. William M Burke
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  2. Xiaohong Jin
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Correspondence to Huey-Jen Lin.

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Burke, W., Jin, X., Lin, HJ. et al. Inhibition of constitutively active Stat3 suppresses growth of human ovarian and breast cancer cells. Oncogene 20, 7925–7934 (2001). https://doi.org/10.1038/sj.onc.1204990

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