Abstract
BackgroundThe acquisition of proliferative and invasive phenotypes is considered a hallmark of neoplastic transformation; however, the underlying mechanisms are less well known. Lipid phosphate phosphatase-3 (LPP3) not only catalyzes the dephosphorylation of the bioactive lipid sphingosine-1-phosphate (S1P) to generate sphingosine but also may regulate embryonic development and angiogenesis via the Wnt pathway. The goal of this study was to determine the role of LPP3 in tumor cells.ResultsWe observed increased expression of LPP3 in glioblastoma primary tumors and in U87 and U118 glioblastoma cell lines. We demonstrate that LPP3-knockdown inhibited both U87 and U118 glioblastoma cell proliferation in culture and tumor growth in xenograft assays. Biochemical experiments provided evidence that LPP3-knockdown reduced β-catenin, CYCLIN-D1, and CD133 expression, with a concomitant increase in phosphorylated β-catenin. In a converse experiment, the forced expression of LPP3 in human colon tumor (SW480) cells potentiated tumor growth via increased β-catenin stability and CYCLIN-D1 synthesis. In contrast, elevated expression of LPP3 had no tumorigenic effects on primary cells.ConclusionsThese results demonstrate for the first time an unexpected role of LPP3 in regulating glioblastoma progression by amplifying β-catenin and CYCLIN-D1 activities.
Highlights
The acquisition of proliferative and invasive phenotypes is considered a hallmark of neoplastic transformation; the underlying mechanisms are less well known
We analyzed an array of 63 glioblastoma tissue sections that were glial fibrillary acidic protein (GFAP) positive; of 63 sections analyzed, 11 sections demonstrated anti-Lipid phosphate phosphatase-3 (LPP3)-RGD antibody immunoreactivity (Figures 2A and 2B)
These data suggest that LPP3 expression is increased in a subset of solid tumors and in U87 and U118 glioblastoma tumor cell lines
Summary
The acquisition of proliferative and invasive phenotypes is considered a hallmark of neoplastic transformation; the underlying mechanisms are less well known. Lipid phosphate phosphatase-3 (LPP3) catalyzes the dephosphorylation of the bioactive lipid sphingosine-1-phosphate (S1P) to generate sphingosine and may regulate embryonic development and angiogenesis via the Wnt pathway. The goal of this study was to determine the role of LPP3 in tumor cells. The lipid phosphate phosphatases (LPPs) have been shown to dephosphorylate sphingosine 1-phosphate (S1P) and its structural homologs to produce metabolic products such as sphingosine, ceramide, and lysophosphatidic acid (LPA) [1,2,3]. LPP1, LPP2, and LPP3 have been studied in various tissues and cell lines [3,4], the role of LPPs in tumor progression is not well understood [1,2,3,4].
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