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

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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Correspondence to Ie-Ming Shih or 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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