Interference with distinct steps of sphingolipid synthesis and signaling attenuates proliferation of U87MG glioma cells

摘要: Glioblastoma is the most common malignant brain tumor, which, despite combined radio- and chemotherapy, recurs invariably fatal for affected patients. Members of sphingolipid (SL) family are potent effectors glioma cell proliferation. In particular sphingosine-1-phosphate (S1P) corresponding G protein-coupled S1P receptors transmit proliferative signals to cells. To investigate contribution proliferation we inhibited first step de novo SL synthesis in p53wt p53mut cells, interfered with signaling specifically U87MG Subunit silencing (RNAi) or pharmacological antagonism (using myriocin) serine palmitoyltransferase (SPT; catalyzing committed biosynthesis) reduced but not GBM cells these observations were accompanied by decreased ceramide, sphingomyelin, content. Inhibition SPT upregulated p53 p21 expression induced an increase early late apoptotic Exogenously added (complexed physiological carriers) increased line, individual members receptor Silencing inhibition ATP-dependent cassette transporter A1 (ABCA1) that facilitates efflux astrocytes attenuated growth. Glyburide-mediated ABCA1 resulted intracellular accumulation raising possibility promotes thereby contributing inside-out signaling. Our findings indicate synthesis, receptor-mediated signaling, ABCA1-mediated could provide targets interfere