Inhibition of Sphingosine Kinase 2 Down-Regulates ERK/c-Myc Pathway and Reduces Cell Proliferation in Human Epithelial Ovarian Cancer

Background: Epithelial ovarian cancer (EOC) is the leading cause of death from female cancers. In our previous study, Sphingosine kinase 2 (SphK2) inhibitor was shown to display anti-EOC activities. The purpose of this study was to further evaluate the expression characteristics and clinical significance of SphK2 in EOC, and to explore the roles and underlying mechanisms of SphK2 in EOC cell survival. Methods: : SphK2 expression was examined by Immunohistochemistry and western blot, and its clinical implications and prognostic significance were analyzed. Cellular proliferation assay and mouse xenograft model was established to confirm the roles of SphK2 in vitro and in vivo. Cell cycle analysis, apoptosis assay and western blot were performed to examine cell cycle progression and apoptosis rate. Gene set enrichment analysis (GSEA) and western blot was used to investigate the downstream signaling pathways related to SphK2 function. Results: : SphK2 expression level was shown to be associated with stage, histological grade, lymph node metastasis and ascite status. More importantly, high SphK2 expression level was a prognostic indicator of overall survival and relapse-free survival. Moreover, knockdown of SphK2 arrested cell cycle progression and inhibited the proliferation of EOC cells both in vitro and in vivo. Furthermore, ERK/c-Myc, the key pathway in EOC progression, was important for SphK2-mediated mitogenic action in EOC cells. Conclusion: Our findings provided the first evidence that SphK2 played a crucial role in EOC proliferation by regulating ERK/c-Myc pathway. SphK2 may serve as a prognostic marker and potential therapeutic target in EOC.