SPHK1 is a novel target of metformin in ovarian cancer.

The role of phospholipid signaling in ovarian cancer (OvCa) is poorly understood. Sphingosine-1-phosphate (S1P) is a bioactive metabolite of sphingosine that has been associated with tumor progression through enhanced cell proliferation and motility. Similarly, sphingosine kinases (SPHK), which catalyze the formation of S1P and thus regulate the sphingolipid rheostat, have been reported to promote tumor growth in a variety of cancers. The findings reported here show that exogenous S1P or overexpression of SPHK1 increased proliferation, migration, invasion and stem-like phenotypes in OvCa cell lines. Likewise, overexpression of SPHK1 markedly enhanced tumor growth in a xenograft model of OvCa, which was associated with elevation of key markers of proliferation and stemness. The diabetes drug, metformin, has been shown to have anti-cancer effects. Here, we found that OvCa patients taking metformin had significantly reduced serum S1P levels, a finding that was recapitulated when OvCa cells were treated with metformin and analyzed by lipidomics. These findings suggested that in cancer the sphingolipid rheostat may be a novel metabolic target of metformin. In support of this, metformin blocked hypoxia-induced SPHK1, which was associated with inhibited nuclear translocation and transcriptional activity of hypoxia-inducible factors (HIF1α and HIF2α). Further, OvCa cells with high SPHK1 were found to be highly sensitive to the cytotoxic effects of metformin while OvCa cells with low SPHK1 were resistant. Together, the findings reported here show that hypoxia-induced SPHK1 expression and downstream S1P signaling promote OvCa progression and that tumors with high expression of SPHK1 or S1P levels might have increased sensitivity to the cytotoxic effects of metformin. Implications: Metformin targets sphingolipid metabolism through inhibiting SPHK1, thereby impeding ovarian cancer cell migration, proliferation and self-renewal.