Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UMLS:C0017636 (glioblastoma)
 18,345 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Ceramide has recently been regarded as a potential mediator of apoptosis. In the present study, the effects of Bcl-2 and Bax on the ceramide-mediated apoptotic pathways were examined in glioma cells overexpressing Bcl-2 or Bax. Etoposide, cisplatin and tumor necrosis factor-alpha induced apoptosis of C6 rat glioma cells which was associated with ceramide formation due to activation of neutral sphingomyelinase, followed by release of mitochondrial cytochrome c into the cytosol and activation of caspases-9 and -3. The growth of C6 cells stably overexpressing either Bcl-2 or Bax was almost equal to that of the vector-transfected cells. Bax overexpression enhanced etoposide-induced apoptosis through acceleration of cytochrome c release and caspases activation. However, Bax had no effect on ceramide formation. Similar findings were obtained in C6 cells and U87-MG human glioblastoma cells which were transiently overexpressed with Bax. In contrast, Bcl-2 overexpression resulted in a retardation of the apoptotic process via prevention of cytochrome c release and caspases activation, and ceramide formation was also blocked when Bcl-2 was highly overexpressed in glioma cells. In addition, transient overexpression of Bcl-xL also exerted inhibitory effects on ceramide formation and apoptotic cell death induced by etoposide. These results indicate that Bax promotes apoptosis regardless of ceramide formation and that Bcl-2 or Bcl-xL prevents ceramide formation by repressing neutral sphingomyelinase as well as ceramide-induced cytochrome c release. Oncogene (2000) 19, 3508 - 3520
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PMID:Influence of Bax or Bcl-2 overexpression on the ceramide-dependent apoptotic pathway in glioma cells. 1091 9

Ceramide is a physiologic regulator of growth and differentiation in mammalian cells. In this study, the relationship between ceramide and FLICE inhibitory protein (FLIP) in the induction of apoptosis in glioblastoma cell lines was investigated. We found that LN215 cells were slightly more sensitive to Fas-mediated apoptosis than LN319 cells, which were more sensitive to ceramide than LN215 cells. FLIP was expressed in LN319 and LN215 cells constitutively, and this expression decreased with treatment of ceramide in LN215 cells, which might cause LN215 cells to be more sensitive to Fas-mediated apoptosis at lower level stimulation. In LN319 cells FLIP levels were not modified by ceramide treatment and the level of cell death induced by anti-Fas antibody was not affected. Our results suggest that FLIP may be down-regulated by low levels of ceramide in LN215 cells, which causes LN215 cells to be more sensitive to Fas-mediated apoptosis, whereas LN319 cells remain resistant.
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PMID:Ceramide increases Fas-mediated apoptosis in glioblastoma cells through FLIP down-regulation. 1263 60

Glycosphingolipids from the ganglio-series are usually classified in four series according to the presence of 0 to 3 sialic acid residues linked to lactosylceramide. The transfer of sialic acid is catalyzed in the Golgi apparatus by specific sialyltransferases that show high specificity toward glycolipid substrates. ST8Sia I (EC 2.4.99.8, SAT-II, SIAT 8a) is the key enzyme controlling the biosynthesis of b- and c-series gangliosides. ST8Sia I is expressed at early developmental stages whereas in adult human tissues, ST8Sia I transcripts are essentially detected in brain. ST8Sia I together with b- and c-series gangliosides are also over-expressed in neuroectoderm-derived malignant tumors such as melanoma, glioblastoma, neuroblastoma and in estrogen receptor (ER) negative breast cancer, where they play a role in cell proliferation, migration, adhesion and angiogenesis. We have stably expressed ST8Sia I in MCF-7 breast cancer cells and analyzed the glycosphingolipid composition of wild type (WT) and GD3S+ clones. As shown by mass spectrometry, MCF-7 expressed a complex pattern of neutral and sialylated glycosphingolipids from globo- and ganglio-series. WT MCF-7 cells exhibited classical monosialylated gangliosides including G(M3), G(M2), and G(M1a). In parallel, the expression of ST8Sia I in MCF-7 GD3S+ clones resulted in a dramatic change in ganglioside composition, with the expression of b- and c-series gangliosides as well as unusual tetra- and pentasialylated lactosylceramide derivatives G(Q3) (II(3)Neu5Ac(4)-Gg(2)Cer) and G(P3) (II(3)Neu5Ac(5)-Gg(2)Cer). This indicates that ST8Sia I is able to act as an oligosialyltransferase in a cellular context.
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PMID:Accumulation of unusual gangliosides G(Q3) and G(P3) in breast cancer cells expressing the G(D3) synthase. 2288 56

Ceramide is composed of sphingosine and a fatty acid found in large concentration within the cell membrane and often acts as a signaling molecule for various functions including programmed cell death. In the present investigation, we observed that C6-ceramide induces p53-dependent apoptosis and effectively killed the Astrocytoma grade4 (Glioblastoma Multiforme) HTB12 cell lines. Ceramide-induced cell death was confirmed by Trypan blue assay which showed about 65% cells dying from ceramide treatment. Apoptosis was confirmed by Caspase3 ELISA assay and DNA fragmentation assay. The p53 induction was confirmed by immunoblot studies. Since C6 Ceramide induces apoptosis in Glioblastoma cells, it may be employed in chemotherapeutic strategy to treat this highly malignant brain cancer.
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PMID:C-6 Ceramide Induces p53 Dependent Apoptosis in Human Astrocytoma Grade4 (Glioblastoma Multiforme) Cells. 2431 43

Ceramide and sphingosine 1-phosphate (S1P) are sphingolipid metabolites with important signaling functions. Ceramides promote apoptosis, whereas S1P favors proliferation, angiogenesis and cell survival. The balance between these opposing signaling functions is referred to as the sphingolipid rheostat. A shift in this balance toward S1P is seen in glioblastoma (GBM) and other cancers, and results in tumor cell survival and resistance to chemotherapy. Sphingosine kinase (SK), the enzyme responsible for transforming sphingosine into S1P, plays the critical role in modulating the balance between S1P and ceramides. Chemotherapeutic agents or radiation therapy may induce short-term responses in GBM patients by increasing ceramide levels. However, we believe that the enzyme SK may cause the increased ceramide to be metabolized to S1P, restoring the abnormally high S1P to ceramide balance, and that this may be part of the reason for the near-100% recurrence rate of GBM. The use of maintenance therapy with an SK inhibitor, in patients with GBM who have tumor reduction or stable disease after therapy, should be investigated.
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PMID:Sphingosine Kinase Inhibitors as Maintenance Therapy of Glioblastoma After Ceramide-Induced Response. 2712 8