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Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway

Oncogene volume 37, pages 3778–3789 (2018)Cite this article

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Abstract

Cell motility and invasiveness are prerequisites for dissemination, and largely account for cancer mortality. We have identified an actionable kinase, spleen tyrosine kinase (SYK), which is keenly tightly associated with tumor progression in ovarian cancer. Here, we report that active recombinant SYK directly phosphorylates cortactin and cofilin, which are critically involved in assembly and dynamics of actin filament through phosphorylation signaling. Enhancing SYK activity by inducing expression of a constitutively active SYK mutant, SYK130E, increased growth factor-stimulated migration and invasion of ovarian cancer cells, which was abrogated by cortactin knockdown. Similarly, SYK inhibitors significantly decreased invasion of ovarian cancer cells across basement membrane in real-time transwell assays and in 3D tumor spheroid models. SYK inactivation by targeted gene knockout or by small molecule inhibition reduced actin polymerization. Collectively, this study reported a new mechanism by which SYK signaling regulates ovarian cancer cell motility and invasiveness, and suggest a target-based strategy to prevent or suppress the advancement of ovarian malignancies.

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Acknowledgements

This study was supported by NIH/NCI grants, RO1CA215483 (I.M.S.), UO1CA200469 (I.M.S.), RO1CA148826 (T.L.W.), R21CA187512 (T.L.W.), K22CA212060 (C.H.H.), KO1-CA166576 (M.I.V.), Richard W. TeLinde Research Program (www.gynecologycancer.org), Ovarian Cancer Research Foundation Alliance (OCRFA) Grant # 458972 (I.M.S.), The Honorable Tina Brozman Foundation (I.M.S. and T.L.W.), TEAL award (T.L.W.), and US Department of Defense Ovarian Cancer Consortium grant W81XWH-11-2-0230 (I.M.S. and T.L.W.).

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Authors and Affiliations

  1. Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins Medical Institutions, Baltimore, MD, 21205, USA

    Yu Yu, Yohan Suryo Rahmanto, Stephanie Gaillard, Ie-Ming Shih & Tian-Li Wang

  2. Department of Pathology, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    Yu Yu, Yohan Suryo Rahmanto, Chuan-Hsiang Huang, Ie-Ming Shih & Tian-Li Wang

  3. Department of Chemical and Biomolecular Engineering, Physical Sciences-Oncology Center, and Institute for NanoBioTechology, Johns Hopkins University, Baltimore, MD, 21218, USA

    Meng-Horng Lee, Pei-Hsun Wu, Jude M. Phillip & Denis Wirtz

  4. Department of Physiology, University of Maryland School of Medicine, Baltimore, MD, USA

    Michele I. Vitolo & Stuart S. Martin

  5. Marlene and Stewart Greenebaum National Cancer Institute Cancer Center, University of Maryland School of Medicine, Baltimore, MD, 21201, USA

    Michele I. Vitolo & Stuart S. Martin

  6. Department of Gynecology and Obstetrics, Johns Hopkins Medical Institutions, Baltimore, MD, 21287, USA

    Stephanie Gaillard, Ie-Ming Shih & Tian-Li Wang

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Yu, Y., Suryo Rahmanto, Y., Lee, MH. et al. Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. Oncogene 37, 3778–3789 (2018). https://doi.org/10.1038/s41388-018-0241-0

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