Lipid Phosphate Phosphatase-3 (LPP3) Knockdown Reduces Tumor Growth by Dampening -Catenin and CYCLIN-D1 Activities

Background: The acquisition of proliferative and invasive phenotypes is considered a hallmark ofneoplastic transformation; however, the underlying mechanisms are less well known. Lipidphosphate phosphatase-3 (LPP3) not only catalyzes the dephosphorylation of the bioactive lipidsphingosine-1-phosphate (S1P) to generate sphingosine but also may regulate embryonicdevelopment and angiogenesis via the Wnt pathway. The goal of this study was to determine the roleof LPP3 in tumor cells.Results: We observed increased expression of LPP3 in glioblastoma primary tumors and in U87 andU118 glioblastoma cell lines. We demonstrate that LPP3-knockdown inhibited both U87 and U118glioblastoma cell proliferation in culture and tumor growth in xenograft assays. Biochemicalexperiments provided evidence that LPP3-knockdown reduced ß-catenin, CYCLIN-D1, and CD133expression, with a concomitant increase in phosphorylated ß-catenin. In a converse experiment, theforced expression of LPP3 in human colon tumor (SW480) cells potentiated tumor growth viaincreased ß-catenin stability and CYCLIN-D1 synthesis. In contrast, elevated expression of LPP3had no tumorigenic effects on primary cells.Conclusions: These results demonstrate for the first time an unexpected role of