LXR-silencing induces apoptosis by glycosphingolipderived ceramide in different tumor cell type

Cell surface ceramide is a key signaling molecule necessary to regulate important cellular processes, like differentiation, proliferation and apoptosis. Its production derives from several sphingolipids, including gangliosides by activity of the plasma membrane glycosidases, like sialidase NEU3, β-HEX, βGAL and β-GLU. We found that several human cancer cell lines (i.e. multiple-myeloma, melanoma and breast cancer) shared the same sensitivity to LXRα signaling abrogation. We focused our attention on one of LXRα target genes, SREBP-1c, a transcription factor regulating de novo lipogenesis, which is the main pathway used by cancer cells for the synthesis of new structural lipids. Both SREBP-1c and its target gene FASN turned out to be down regulated in shLXRα-sensitive but not in shLXRα-insensitive cells. Finally, we have found in the shLXRα-sensitive cells an increase of apoptotic cell death due to an increase of PM ceramide up to 3 times with respect to the shLXRα-insensitive cells. We also observe a reduction in ganglioside GM3, suggesting that ceramide is because of the activity of PM sialidase NEU3, β-GAL and β-GLU. These data suggest that in shLXRα-sensitive cells the tumor-promoting role of LXRα might be due to an effect on the SREBP-1c-driven de novo lipogenesis. FASN inactivation could be responsable for a reorganization of cell membrane given a decrease in the synthesis of FA, therefore an alteration of lipid metabolism: increase in glycohydrolase activity and in PM GM3, LacCer, GlcCer and pro-apoptotic ceramide. This pathway may represent a novel potential drug-target in multiple-myeloma and other tumors.