Different mechanisms are involved in apoptosis induced by melanoma gangliosides on human monocyte-derived dendritic cells

Tumor escape is linked to multiple mechanisms, notably the liberation, by tumor cells, of soluble factors that inhibit the function of dendritic cells (DC). We have shown that melanoma gangliosides impair DC differentiation and induce their apoptosis. The present study was aimed to give insight into the mechanisms involved. DC apoptosis was independent of the catabolism of gangliosides since lactosylceramide did not induce cell death. Apoptosis induced by GM3 and GD3 gangliosides was not blocked by inhibitors of de novo ceramide biosynthesis, whereas the acid sphingomyelinase inhibitor desipramine only prevented apoptosis induced by GM3. Furthermore, our results suggest that DC apoptosis was triggered via caspase activation, and it was ROS dependent with GD3 ganglioside, suggesting that GM3 and GD3 induced apoptosis through different mechanisms

Production of Multiple Brain-Like Ganglioside Species Is Dispensable for Fas-Induced Apoptosis of Lymphoid Cells

Activation of an acid sphingomyelinase (aSMase) leading to a biosynthesis of GD3 disialoganglioside has been associated with Fas-induced apoptosis of lymphoid cells. The present study was undertaken to clarify the role of this enzyme in the generation of gangliosides during apoptosis triggered by Fas ligation. The issue was addressed by using aSMase-deficient and aSMase-corrected cell lines derived from Niemann-Pick disease (NPD) patients. Fas cross-linking elicited a rapid production of large amounts of complex a- and b-series species of gangliosides with a pattern and a chromatographic behavior as single bands reminiscent of brain gangliosides. The gangliosides were synthesized within the first ten minutes and completely disappeared within thirty minutes after stimulation. Noteworthy is the observation that GD3 was not the only ganglioside produced. The production of gangliosides and the onset of apoptotic hallmarks occurred similarly in both aSMase-deficient and aSMase-corrected NPD lymphoid cells, indicating that aSMase activation is not accountable for ganglioside generation. Hampering ganglioside production by inhibiting the key enzyme glucosylceramide synthase did not abrogate the apoptotic process. In addition, GM3 synthase-deficient lymphoid cells underwent Fas-induced apoptosis, suggesting that gangliosides are unlikely to play an indispensable role in transducing Fas-induced apoptosis of lymphoid cells

Dysregulated Expression of Glycolipids in Tumor Cells: From Negative Modulator of Anti-tumor Immunity to Promising Targets for Developing Therapeutic Agents

Glycolipids are complex molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found the gangliosides, which are sialylated glycolipids ubiquitously distributed on the outer layer of vertebrate plasma membranes. Changes in the expression of certain species of gangliosides have been described to occur during cell proliferation, differentiation and ontogenesis. However, the aberrant and elevated expression of gangliosides has been also observed in different types of cancer cells, thereby promoting tumor survival. Moreover, gangliosides are actively released from the membrane of tumor cells, having a strong impact on impairing anti-tumor immunity. Beyond the undesirable effects of gangliosides in cancer cells, a substantial number of cancer immunotherapies have been developed in recent years that have used gangliosides as the main target. This has resulted in successful immune cell- or antibody-responses against glycolipids, with promising results having been obtained in clinical trials. In this review, we provide a general overview on the metabolism of glycolipids, both in normal and tumor cells, as well as examining glycolipid-mediated immune modulation and the main successes achieved in immunotherapies using gangliosides as molecular targets

Rôle des gangliosides, et en particulier du GD3, dans la biologie de la cellule (étude de l'immunogénicité de GD3 et mise en évidence d'une biosynthèse de gangliosides lors de l'apoptose)

Nous avons mis en évidence par GC-MS dans les tumeurs de mélanome du ganglioside GM3 dont l'acide sialique est sous forme de lactone interne 1-7, ainsi que du GD3 dont l'acide sialique est N-desacétylé. Nous avons étudié le mimétisme moléculaire de répliques peptidiques du ganglioside GD3 isolées à partir d'une banque de phages filamenteux avec un anticorps antiGD3 IgG3- . L'immunisation de souris avec ces peptides a produit deux anticorps monoclonaux anti-GD3 dont une IgG1- qui se fixe aux cellules exprimant GD3 et une IgG3- La biosynthèse des sphingolipides pendant le processus apoptotique a aussi été étudiée. Nous avons montré que plusieurs types de cellules synthètisent en quelques minutes après traitement apoptogène une très grande quantité de gangliosides qu'elles dégradent dans les minutes suivantes. Les espèces moléculaires produites différent selon le type de cellules. Les inhibiteurs d'apoptose z-VAD et DPI annulent cette biosynthèse, ainsi que la cyclosérine qui bloque la sérine palmitoyltransférase.LYON1-BU.Sciences (692662101) / SudocSudocFranceF