CSE1L in enhancing the effect of defactinib on gastric cancer cells via the inhibition of FAK phosphorylation

Background: Chromosome segregation 1 like (CSE1L) overexpression can promote proliferation and migration in cancer. In previous study, we found that CSE1L expression was higher in gastric cancer (GC) tissues compared to normal tissues. However, the biological function and molecular mechanism of CSE1L in GC remains unclear. In this study, we investigate the function of CSE1L in GC biology and its related molecular mechanisms and therapeutic potentials. Methods: Transcriptome data from public databases were used to assess CSE1L messenger RNA (mRNA) expression levels in GC. A total of 83 pairs of GC surgical samples were evaluated to determine CSE1L protein expression levels. CSE1L was knocked out in MGC-803 and overexpressed in BGC-823 to evaluate its biological function in GC cells. RNA sequencing (RNA-seq) was used to identify the signaling pathways regulated by CSE1L and the underlying molecular mechanisms, and the transcriptome data were validated. Western blotting and immunofluorescence were used to clarify the regulatory effect of CSE1L on phosphorylated focal adhesion kinase (p-FAK). Results: CSE1L mRNA was increased in patients with GC, and the high expression of CSE1L was associated with poor prognosis in these patients. Protein levels of CSE1L were also increased in GC surgical samples. CSE1L promoted cell proliferation, cell migration, cell invasion, clone formation, and adhesion ability in GC cells. RNA-seq results suggested that CSE1L upregulated the focal adhesion pathway, which was verified at the mRNA level and protein level. Moreover, CSE1L upregulated p-FAK tyrosine 397 [p-FAK (Y397)] and enhanced the efficacy of defactinib. After the knockout of CSE1L, the killing effect of defactinib on GC cells was intensified. Conclusions: CSE1L is a potential biomarker for evaluating the prognosis of patients with GC. Knockdown of CSE1L can enhance the efficacy of defactinib by inhibiting p-FAK (Y397), which may be a synergistic target of defactinib.