Molecular Mechanisms of GD3-Induced Apoptosis in U-1242 MG Glioma Cells

Abstract

An increasing amount of evidence indicates that the disialoganglioside GD3 is involved in apoptosis in many cell lines. Our previous studies demonstrated that endogenous GD3 expression induced apoptosis in U-1242 MG glioma cells transfected with the GD3 synthase gene (U1242MG-GD3 cells). In this paper, we present further investigations on the molecular mechanisms of GD3-induced apoptosis in this cell line. We found that endogenously synthesized GD3 localizes to the caveolae of this cell line, where it promotes the localization of death receptor 5 (DR5), tumor necrosis factor receptor-1 (TNF-R1), and Fas (Apo-1) to the caveolae. In addition, caspase-8 was translocated to the caveolar fraction and cleaved; the cleaved proteins were then re-located into the high density fractions. However, GD3 had no effect on the distribution of the adapter protein Fas-associated death domain (FADD). We conclude that GD3 functions as a regulatory molecule early in the extrinsic apoptosis pathway.

Podocyte Pathology and Nephropathy – Sphingolipids in Glomerular Diseases

“…In other studies, an important role of membrane-associated ASMase was suggested in Fas-mediated apoptosis as activation of ASMase leads to the generation of free ceramide, which then can be converted to GD3 (60, 61). A similar pathway has been recently described in TNFα-mediated apoptosis (62, 63). Significant 9- O -acetyl GD3 accumulation, together with increases in GM2 and GM4 gangliosides in glomerular cells was also observed after low level and long term lead exposure and was associated with decreased apoptosis in glomerular cells suggesting that GD3-O acetylation could represent a new strategy to attenuate apoptosis in renal glomerular cells and contribute to cell survival as observed during lead exposure (64).…”

Microarray analysis of altered sphingolipid metabolism reveals prognostic significance of sphingosine kinase 1 in breast cancer

“…Omran and colleques described an involvement of GD3 in apoptosis in U-1242 glioma cells [24]. Zeng et al [25] found evidence for an association between GD3 Ganglioside and tumor progression and even development of metastatic potential.…”

Regulation of Death Receptor Signaling by S-Palmitoylation and Detergent-Resistant Membrane Micro Domains—Greasing the Gears of Extrinsic Cell Death Induction, Survival, and Inflammation

“…This supports our data, showing that upon pharmacological inhibition of APT2, TNF-R1 stays at the PM (putatively in caveolae) and induces ceramide production via nSMase in U937 cells. The Yates group showed that TNF-R1, CD95, and DR5 are located in caveolin-1 positive DRM fractions of U-1242 glioma cells by default and that TRAIL treatment invoked caspase-8 recruitment and activation in this compartment [ 49 , 50 ]. D’Alessio et al suggested a TNF-R1-membrane-proximal sequence, close to C248, as we recently reported, targeting it to caveolae and that TNF-R1 internalization requires caveolae localization [ 51 ].…”