SLFN5 suppresses cancer cell migration and invasion by inhibiting MT1-MMP expression via AKT/GSK-3β/β-catenin pathway.

Human SLFN5 inhibits invasions of IFNα-sensitive renal clear-cell carcinoma and melanoma cells. However, whether this inhibition is confined to these IFNα-sensitive cancers is unclear. Here we show that SLFN5 expressions on both mRNA and protein levels are significantly higher in non/low-invasive cancer cell lines (breast cancer cell line MCF7, colorectal cancer cell line HCT116 and lung cancer cell line A549) than in highly-invasive cancer cell lines (fibrosarcoma cell line HT1080 and renal clear cell cancer cell line 786-0). SLFN5 knockdown in non/low-invasive cancer cell lines enhanced MT1-MMP expression and increased migration and invasion in vitro, and in vivo. Furthermore, SLFN5 overexpression in HT1080 and 786-0 inhibited MT1-MMP expression and repressed migration and invasion. MT1-MMP is instrumental in SLFN5-controlled inhibition of cancer cell migration and invasion, as shown by MT1-MMP-knockdown and -overexpression analyses. SLFN5 knockdown activated AKT/GSK-3β/β-catenin pathway by promotion AKT phosphorylation and subsequent GSK-3β phosphorylation, further β-catenin translocation into nucleus as un-phosphorylated protein at Ser33, 37 and 45 and Thr41 sites. This is the first study to report that SLFN5 inhibits cancer migration and invasiveness in several common cancer cell lines by repressing MT1-MMP expression via the AKT/GSK-3β/β-catenin signalling pathway, suggesting that SLFN5 plays wide inhibitory roles in various cancers.