SphK1 inhibitor SKI II inhibits the proliferation of human hepatoma HepG2 cells via the Wnt5A/β-catenin signaling pathway

Aim: Sphingosine 1-phosphate (S1P) promotes cell growth, proliferation and survival. Sphingosine kinase 1 (SphK1), which converts sphingosine to S1P, is a key promoter in cancer. We previously found that the SphK1 inhibitor II (SKI II), suppresses the cell growth and induces apoptosis in human hepatoma HepG2 cells. However, the precise regulatory mechanism and signaling pathway on SKI II inhibiting tumor growth remains unknown. Main methods: The expressions of beta-catenin and related molecules of Wnt/beta-catenin signal were detected by western blot in HepG2 cells. And the mRNA expression of beta-catenin was detected by RT-PCR. The Wnt5A gene was silenced by siRNA. The colony formation was determined by staining with crystal violet. And the cell growth was examined by SRB assay and BrdU assay. Key findings: We found that SKI II decreased the expression of beta-catenin and the downstream molecules of beta-catenin signal pathway and promotes the beta-catenin degradation. In addition, SKI II induced the expression of Wnt5A, and then triggered beta-catenin degradation. Furthermore, silencing Wnt5A decreased the anti-tumor effects of SKI II through recovering the expressions of beta-catenin and downstream molecules of beta-catenin signal pathway. Significance: SKI II-induced downregulation of HepG2 cell proliferation was associated with Wnt signaling pathway through Wnt5A-mediated beta-catenin degradation. Our study revealed that a novel signal pathway was involved in SKI II-inhibited cell proliferation in human hepatoma cells. (C) 2016 Elsevier Inc. All rights reserved.