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

Ovarian cancer 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 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, SYK(130E), 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 through basement membrane matrix in a real-time transwell assays and in a 3-D tumor spheroid model. SYK inactivation by gene knockout or by small molecule inhibition reduced actin polymerization. Collectively, the results reported here identify a new mechanism by which SYK signaling regulates ovarian cancer cell motility and invasiveness, and pinpoint a target-based strategy to prevent or suppress the advancement of ovarian malignancies.