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

Yu Yu, Yohan Suryo Rahmanto, Meng Horng Lee, Pei Hsun Wu, Jude M. Phillip, Chuan Hsiang Huang, Michele I. Vitolo, Stephanie Gaillard, Stuart S. Martin, Denis Wirtz, Ie Ming Shih, Tian-Li Wang

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Pages (from-to)1-12
Number of pages12
JournalOncogene
DOIs
StateAccepted/In press - Apr 11 2018

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Protein-Tyrosine Kinases
Ovarian Neoplasms
Cortactin
Neoplasms
Cell Movement
Actin Depolymerizing Factors
Gene Knockout Techniques
Syk Kinase
Actin Cytoskeleton
Basement Membrane
Polymerization
Actins
Intercellular Signaling Peptides and Proteins
Phosphotransferases
Phosphorylation
Mortality

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. / Yu, Yu; Suryo Rahmanto, Yohan; Lee, Meng Horng; Wu, Pei Hsun; Phillip, Jude M.; Huang, Chuan Hsiang; Vitolo, Michele I.; Gaillard, Stephanie; Martin, Stuart S.; Wirtz, Denis; Shih, Ie Ming; Wang, Tian-Li.

In: Oncogene, 11.04.2018, p. 1-12.

Research output: Contribution to journalArticle

Yu, Yu ; Suryo Rahmanto, Yohan ; Lee, Meng Horng ; Wu, Pei Hsun ; Phillip, Jude M. ; Huang, Chuan Hsiang ; Vitolo, Michele I. ; Gaillard, Stephanie ; Martin, Stuart S. ; Wirtz, Denis ; Shih, Ie Ming ; Wang, Tian-Li. / Inhibition of ovarian tumor cell invasiveness by targeting SYK in the tyrosine kinase signaling pathway. In: Oncogene. 2018 ; pp. 1-12.
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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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