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PubMed2001

Influence of gangliosides or LPS-like gangliosides on the tumoricidal activity of adherent leukocytes.

We previously showed that highly metastatic clones derived from the poorly metastatic human melanoma cell line M4Be are very radiosensitive provided that they are deficient in complex gangliosides. Here, we report that the highly metastatic clone 4 appears more sensitive to activated adherent leukocytes than M4Be via a transmembrane TNF-alpha-dependent mechanism. Adherent leukocytes (AL) were freshly isolated from different blood donors and were activated with Esherichia coli lipopolysaccharide (LPS). These AL contain 80% (73-93%) monocytes, 15% (6-20%) B lymphocytes and 5% (1-8%) T lymphocytes. The tumour cell survival following contact with AL was estimated with a clonogenic assay where isolated tumour cells were plated for 14 days with AL. We show on the one hand that either exogenous bovine brain GM1 gangliosides or Campylobacter jejuni LPS with GM1-like structure (LPS-like GM1) significantly decrease the hypersensitivity of clone 4 to AL. On the other hand, the cleaving with neuraminidase of more than 50% of the sialic residues bound to endogenous gangliosides in resistant M4Be cells significantly increases their sensitivity to AL. Thus, our highly metastatic cells appear both very sensitive to activated AL when they are deficient in complex gangliosides and resistant to AL when they are transiently exposed to exogenous gangliosides or LPS-like gangliosides. These in vitro data may reflect the paradoxidal behaviour of highly metastatic cells in vivo which appear both very sensitive to physiological stresses and able to survive to form secondary tumours.

Adult↗
PubMed1983

Ganglioside-induced neuritogenesis: verification that gangliosides are the active agents, and comparison of molecular species.

Gangliosides were previously reported to induce neuritogenesis in primary neuronal cultures and in some neurally derived cell lines. Because isolated gangliosides usually contain variable quantities of peptides, we investigated the possibility that neurite-stimulating activity could be caused by these contaminants. Ganglioside preparations from bovine brain and other sources were subjected to a three-step purification procedure that eliminated at least 95% of the contaminating peptides. These purified preparations retained their capacity to induce extensive neurite growth in neuro-2A murine neuroblastoma. Proteolytic digestion and a number of additional procedures were used to reduce residual contamination further without loss of activity. Several crude ganglioside samples had negative effects on neurite development until freed of their inhibitory factors, which were derived from the tissue and/or introduced during laboratory operations. This was particularly evident for bovine white matter gangliosides whose activity increased in proportion to peptide removal. When carefully purified, virtually all of 11 different gangliosides tested were highly active, with the possible exception of GM4, which demonstrated only moderate activity in a limited number of tests. All of the neutral glycolipids tested, as well as sulfatides and free sialic acid, were inactive.

Animals↗
PubMed1984

Promotion of neuritogenesis in mouse neuroblastoma cells by exogenous gangliosides. Relationship between the effect and the cell association of ganglioside GM1.

Ganglioside GM1 promoted neuritogenesis of neuroblastoma cells, neuro-2a clone, in monolayer culture. GM1 bound to neuro-2a cells in three distinct forms, one removable by treatment with serum-containing solutions, one serum-resistant and labile to trypsin treatment, and one resistant to serum and trypsin treatments. The proportions among the three forms of cell-associated GM1 varied in relation to duration of exposure to ganglioside, ganglioside concentration in the medium, and number of cells in culture. The form removable by serum was predominant at the initial stages of association and at the highest ganglioside concentrations (over 10(-6)M); the trypsin-labile and -stable forms tended to increase with increasing cell number and decreasing ganglioside concentration. The neuritogenic effect of GM1 was higher when neuro-2a cells were incubated for 24 h in the presence of GM1 and fetal calf serum. Under this condition the percentage of neurite-bearing cells increased from 11% of control to 62% at the optimal ganglioside concentration of 10-4M. The effect was still present, although to a lower extent (from 11% to 28% of neurite-bearing cells), when cells were first exposed for only 2 h to GM1, then washed and incubated for 24 h in the presence of fetal calf serum. The trypsin-labile and -stable forms of cell-associated GM1 had a fundamental role in the effect, whereas the form removable by serum was not involved. The preparation of GM1 used was extremely pure (99%) and, in particular, had a peptide contamination, if any, less than 1:20,000-1:50,000.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1984

Studies on bioactive gangliosides: II. Requirement of ganglioside GD1a for prolonged GQ1b-driven nerve growth promotion in neuroblastoma cell lines.

The novel effects of gangliosides from human brain on the number of nuclei of nerve cells and neurite outgrowth were studied in cultures of human neuroblastoma cell lines GOTO and NB-1. Ganglioside GQ1b at a nanomolar level stimulated cell proliferation and neurite outgrowth during culture for 24 hours, as reported previously [J Biochem 94: 303-306, 1983]. Although the neurite promoting activity of GQ1b was similar to those of total human brain gangliosides (GS) and nerve growth factor (NGF), its activity on cell proliferation did not persist on longer culture; that is, the number of GQ1b-treated cells rapidly decreased to the control level during culture for 48 or 72 hours. In contrast, on treatment with GS or NGF, the number of cell nuclei increased continuously during prolonged culture. These results showed that either some other molecular species of ganglioside(s) than GQ1b or other substances such as proteins present in the GS fraction were responsible for the long-term activity. Studies on the GS fraction after its treatment with proteases and neuraminidases revealed that ganglioside GD1a (20 ng/ml) had the ability to prolong the activity of GQ1b. Namely, GQ1b and GD1a gangliosides cooperated in maintaining the number of nuclei in long-term cultures of neuroblastoma cell lines.

Cell Differentiation↗
PubMed1994

Branched monosialo gangliosides of the lacto-series isolated from bovine erythrocytes: characterization of a novel ganglioside, NeuGc-isooctaosylceramide.

We report the isolation, purification, and structural characterization of three monosialo gangliosides (G-1, G-2, and G-3) from bovine erythrocytes. Each of the purified compounds migrates as a single band on thin-layer chromatography in three solvent systems. All three gangliosides contain ceramide (Cer) as the lipid protein, with d18:1 sphingosine as the predominant long-chain base and with C18:0, C18:1, C20:0, C20:1, and C22:1 fatty acids, as determined by gas chromatography. The structural characterization of the carbohydrate moieties of G-1, G-2, and G-3 involved glycosyl composition analysis, methylation studies, sequential exoglycosidase hydrolysis, and one-dimensional 1H NMR spectroscopy of the native gangliosides. Furthermore, the oligosaccharides were released from the sphingolipids by endoglycoceramidase and fully sequenced by one- and two-dimensional 1H NMR spectroscopy in conjunction with fast-atom-bombardment mass spectrometry and exoglycosidase treatment. The structures are as follows: [formula: see text] Gangliosides such as G-1, G-2, and G-3, with branched oligosaccharide chains comprising a number of N-acetyllactosamine (Gal-GlcNAc) moieties, are abundant in erythrocytes from various mammalian species. The simultaneous occurrence of sialic acid and alpha-galactose as terminal sugars in these gangliosides, however, is relatively rare. Specifically, G-1 represents a ganglioside with a novel structure.

Amidohydrolases↗
PubMed1977

Ganglioside content and pattern in human gliomas in culture. Correlation of morphological changes with altered gangliosides.

The ganglioside level and pattern of human gliomas in monolayer cultures were examined. These gliomas revealed morphological variations that correlated with several features of ganglioside analysis. Glioblastoma lines TC 178 and TC 501 that morphologically had changed during extended subculture revealed reduced amounts and a simplified pattern of gangliosides with almost total loss of the characteristic brain complex gangliosides. In contrast, two glioblastoma lines TC 526 and TC 593, as well as the oligodendroglioma line TC 620 showed brain-like gangliosides and the cells in these cultures had maintained their characteristic morphology observed during early subcultures. The possibility that altered ganglioside levels occur in conjunction with morphological changes after propagation in vitro is discussed.

Brain Neoplasms↗
PubMed1990

Patterns of endogenous gangliosides and metabolic processing of exogenous gangliosides in cerebellar granule cells during differentiation in culture.

The qualitative and quantitative pattern of endogenous gangliosides and the routes of metabolic processing of exogenous GM1, 3H labeled in the sphingosine moiety (Sph-3H GM1) were studied in cerebellar granule cells during differentiation in vitro. During the first 7-8 days in culture the ganglioside content markedly increased, and the qualitative pattern showed, in percentage terms, a drastic decrease of GD3 and a marked increase of GD2, O-Ac-GT1b, O-Ac-GQ1b and GQ1b. After pulse with (Sph-3H) GM1, at all the investigated days in culture, different radiolabelled lipids were formed indicating that taken up exogenous GM1 was degraded and that its catabolic fragments, and partly GM1 itself, were used for biosynthetic purposes; moreover radioactive water was measured in the culture medium during chase indicating that labelled sphingosine underwent also degradation. The uptake of exogenous GM1 and the extent of its metabolic processing per cell unit increased during differentiation: a) GM2 was the major metabolic product and was relatively more abundant at 2 than 7 days in culture; b) the percentage of metabolites of biosynthetic origin over total metabolites increased during differentiation, especially at the short pulse times; c) among the metabolites of anabolic origin sphingomyelin equalled gangliosides at 2 days, whereas it was largely overcome by gangliosides at 7 days in culture; d) at 4 and 7 days in culture a radioactive substance, not yet identified, was present, whereas no trace of it was found at 2 days. In conclusion, cerebellar granule cells in culture feature a different pattern of endogenous gangliosides and display different ability to metabolically process exogenous GM1 ganglioside in the undifferentiated and fully differentiated stage.

Animals↗
PubMed1984

Total gangliosides, ganglioside species and the activity of neuraminidase in different brain regions and spinal cord of normal and undernourished rats.

Total gangliosides, their concentrations and the distribution of individual ganglioside species were determined in the spinal cord, pons-medulla, midbrain, cerebellum, hypothalamus, cerebral cortex, olfactory lobes and the rest of the forebrain, of 18- and 33-day-old normal and food-restricted and rehabilitated rats. The activity of neuraminidase in the different regions of the brain and spinal cord was determined. Differences in total gangliosides as well as individual species in different regions of the brain were observed. Among brain regions, while total ganglioside content was significantly reduced in the case of the cerebellum, the hypothalamus was the most affected in the distribution of ganglioside species and the activity of neuraminidase was decreased. The significance of the distribution of ganglioside species in different brain regions in relation to the activity of neuraminidase is discussed.

Animals↗
PubMed1995

Identification and synthetic pathway of sialyl-Lewisx-containing neolacto-series gangliosides in lens tissues. 1. Characterization of gangliosides in human senile cataractous lens.

Human lens accumulates gangliosides in association with aging and senile cataract progression. In this study we purified and characterized five major gangliosides in human cataractous lenses. Structural analyses and immunological studies revealed the presence of ganglio-series gangliosides, GM3, GM2, GM1 and GD1a, and a sialyl-Lewisx-containing neolacto-series ganglioside, NeuAc alpha 2-3Gal beta 1-4(Fuc alpha 1-3)GlcNAc beta 1-3Gal beta 1-4Glc beta 1-1ceramide (IV3NeuAcIII3FucnLc4). Slow-moving gangliosides, although minor components, were also found to have sialyl-Lewisx-related structures, based on anti-Lewisx antiserum binding to their asialo forms. However, sialyl-paragloboside, a possible precursor of the sialyl-Lewisx ganglioside, was not identified.

Aged↗
PubMed1995

Interleukin-3-associated expression of gangliosides in mouse myelogenous leukemia NFS60 cells introduced with interleukin-3 gene: expression of ganglioside GD1a and key involvement of CMP-NeuAc:lactosylceramide alpha 2-->3-sialyltransferase in GD1a expression.

Murine interleukin-3 (IL-3)-associated expression of gangliosides has been investigated using a gene transfection technique. A murine IL-3 cDNA was introduced into the parental NFS60-17 cells that was exclusively dependent on IL-3. We analyzed the glycosphingolipids from the parental cells and the transfected cells by fast atom bombardment mass spectrometry analyses and/or immunostaining techniques using specific antibodies. Two major gangliosides, IV3NeuAc-GgOse4Cer (GM1b) and IV3-NeuAc,III6NeuAc-GgOse4Cer (GD1 alpha), were expressed, in the parental cells. By contrast, in the IL-3 gene-transfected cells, a ganglioside IV3NeuAc,II3NeuAc-GgOse4Cer (GD1a) was strikingly expressed, in addition to GM1b and GD1 alpha that were already present in the parental cells. In spite of various IL-3-secreting capabilities, all transfectants investigated have exhibited the same ganglioside patterns and expressed GD1a. Furthermore, the appearance of GD1a was a consequence of the up-regulation of a single glycosyltransferase, CMP-NeuAc:lactosylceramide alpha 2-->3-sialytransferase (GM3 synthase). Activities of the other downstream glycosyltransferases that were involved in GD1a synthesis were not significantly different between the parental and the transfected cells. According to these data, the progression of tumor stage by the acquisition of autonomous cell growth ability after IL-3 gene transfection resulted in dramatic changes in cell surface gangliosides and their biosynthetic pathways. GD1a could be considered as an IL-3-associated ganglioside and was expressed in a tight connection with a single glycosyltransferase (GM3 synthase) up-regulation and with IL-3 expression in murine myelogenous leukemia cells.

Animals↗
PubMed1981

Fluorospectroscopic studies of various ganglioside and ganglioside--lecithin dispersions. Steady-state and time-resolved fluorescence measurements with 1,6-diphenyl-1,3,5-hexatriene.

Molecular motions of 1,6-diphenyl-1,3,5-hexatriene (DPH) in gangliosides (GM3, GM2, GM1, GD1a, and GD1b), GA1 glycosphingolipid, and dipalmitoyl-sn-glycero-3-phosphorylcholine (DPPC)--ganglioside mixed dispersions were studied by using techniques of steady-state and nano-second time resolved fluorescence measurements in the temperature range of 20--50 degrees C. The total fluorescence decay s(t) was approximated to a best-fit curve of double-exponential decays, and two fluorescence lifetimes were obtained. The values of the shorter fluorescence lifetime in dispersions composed of a single glycosphingolipid component approached those of the longer one on addition of DPPC. The molecular arrangement or microheterogeneity of the hydrocarbon region surrounding DPH molecules changed depending on the ratio of DPPC to ganglioside molecules and on the temperature. The steady-state anisotropy rs in dispersions composed of a single glycosphingolipid component exhibited smooth changes, not abrupt ones, in the temperature range, in contrast to that in DPPC liposomes. In the various glycosphingolipid dispersions studied, the motion of DPH molecules was the most restricted in the GA1 dispersion. Sialic acid linked to the neutral sugar backbone influenced the hydrophobic region and increased the motion of DPH molecules. In the gangliosides tested, the motion of DPH molecules in the hydrophobic region of GM1 ganglioside was found to be the most restricted. These comparative studies indicate that the ultimate and/or penultimate carbohydrate moieties of the neutral sugar backbone of gangliosides and the topographical difference in the locations of the sialic acid linkage influence the integrity of the membranes including the hydrophobic region.

Animals↗
PubMed2002

Anti-ganglioside antibodies bind with enhanced affinity to gangliosides containing very long chain fatty acids.

Gangliosides function in both physiological and pathological molecular recognition. Although much research has focused on the role of ganglioside glycans in recognition, fewer studies have addressed the role of the ceramide moiety. Ceramides of major brain gangliosides are composed predominantly of monounsaturated 18-carbon and 20-carbon long chain bases with a saturated 18-carbon fatty acid amide. In contrast, gangliosides of X-linked adrenoleukodystrophy patients are characterized by abnormal very long chain fatty acids that are proposed to be associated with autoimmune inflammation. In the current study we synthesized and characterized derivatives of the major brain ganglioside GD1a bearing defined very long chain fatty acid amides (C24:0, C24:1, and C26:0). When tested in a solid phase binding assay in the presence of auxiliary membrane lipids, GD1a species with long chain fatty acids were up to 8-fold more potent than normal brain GD1a in binding four different anti-GD1a monoclonal antibodies. These data support the hypothesis that gangliosides bearing very long chain fatty acids are differentially displayed on membranes, which may lead to altered antigenicity.

Animals↗
PubMed1978

The biosynthesis of brain gangliosides. Ganglioside-glycosylating activity in rat brain neuronal perikarya fraction.

Rat brain homogenate and the synaptosmal and neuronal perikarya fractions from 17-day-old rats were compared for their activities in sialosylating endogenous gangliosides and transferring N-acetylneuraminic acid and galactose to several glycolipids in vitro. The sialosylation of endogenous gangliosides and the activities of sialosyltransferases acting either on lactosylceramide or haematoside as acceptors, as well as galactosyltransferase acting on Tay-Sachs ganglioside as acceptor, were between 3-and 12-fold higher in the neuronal perikarya fraction than in whole homgenate on a protein or ganglioside basis. The activities found in the synaptosomal fraction were negligible. No evidence was found to indicate that the low activities in this fraction were due to the presence of inhibitors of the transfer activities or to inacessibility of the substrates to their respective enzymes. These findings, and the time course of labelling of gangliosides of the neuronal perikarya and synaptosomes from rats that received an injection of N-[3H]acetylmannosamine, indicate that the main cellular site of glycosylation of neuronal gangliosides is in the neuronal perikarya.

Animals↗
PubMed2002

Ganglioside modulation regulates epithelial cell adhesion and spreading via ganglioside-specific effects on signaling.

Gangliosides are implicated in regulating cell adhesion and migration on fibronectin by binding with the alpha(5) subunit of alpha(5)beta(1) integrin. However, the effects of gangliosides on cell spreading and related signaling pathways are unknown. Increases in gangliosides GT1b and GD3 inhibited spreading on fibronectin, concurrent with inhibition of Src and focal adhesion kinase. Although antibody blockade of GT1b or GD3 function and gene-modulated ganglioside depletion stimulated spreading and activated Src and focal adhesion kinase, the augmented spreading by disruption of GT1b function, but not by disruption of GD3 function, was inhibited by blockade of Src and focal adhesion kinase activation. In contrast, inhibitors of protein kinase C prevented the stimulation of spreading by GD3 functional inhibition, but not by GT1b functional blockade. Modulation of either GT1b or GD3 content affected phosphoinositol 3-kinase activation, and inhibition of this activation reversed the stimulation of cell spreading by anti-GD3 antibody, anti-GT1b antibody, and ganglioside depletion, suggesting that phosphoinositol 3-kinase is an intermediate in both the FAK/Src and protein kinase C pathways that lead to cell spreading. These studies demonstrate that epithelial cell ganglioside GT1b modulates cell spreading through alpha(5)beta(1)/FAK and phosphoinositol 3-kinase signaling, whereas GD3-modulated spreading appears to involve phosphoinositol 3-kinase-dependent protein kinase C signaling.

Base Sequence↗
PubMed1994

Effect of brefeldin A on ganglioside metabolism in cultured neurons: implications for the intracellular traffic of gangliosides.

The effect of BFA on the metabolic processing and intracellular traffic of gangliosides was studied in cerebellar granule cells, fed in culture for different periods with radiolabeled ganglioside GM1. The following results were obtained: (a) degradation of taken-up GM1 was markedly inhibited by BFA; this effect was rapid, reversible, and affected by reduced temperature, ATP depletion, and microtubule disruption: (b) direct glycosylation of internalized GM1 to GD1a was completely blocked by BFA; (c) the portion of GM1 that escaped BFA inhibition was degraded with formation of sphingosine, that was recycled for the biosynthesis of less glycosylated glycolipids (glucosyl-ceramide, GM3 and GD3); (d) in BFA-treated cells highly glycosylated gangliosides were undetectable, and the formation of sphingomyelin from liberated sphingosine was markedly reduced. These results suggest that, in the cells used: (a) the delivery of endocytosed gangliosides to lysosomes, (b) the flow of poorly glycosylated glycolipids from the Golgi stacks to the trans-Golgi network, and (c) the direct transport of part of endocytosed gangliosides to the late sites of glycosylation (possibly TGN) are mediated by BFA-sensitive vesicles. We propose that in cultured granule cells a BFA-sensitive mechanism regulates ganglioside traffic to and from the plasma membrane.

Animals↗
PubMed1992

Gangliosides in bovine milk. Changes in content and distribution of individual ganglioside levels during lactation.

Bovine milk undergoes changes in its ganglioside contents during the different stages of lactation. These contents are higher in colostrum (7.5 mg of lipid-bound NeuAc/kg) than in transitional (2.3 mg) or mature (1.4 mg) milk. The sialic acid content of milk follows a similar profile to that of gangliosides with the highest content during the first few days post partum followed by a gradual decrease towards the end of the period studied. When the individual distribution of gangliosides was examined throughout the course of lactation, several changes were also found. GD3 is the major ganglioside (about 60-70%) found; its content decreases from the first to the fifth day, increasing towards the end of the period considered. GM3, GD3 and GT3, sialyllactosylceramide-containing gangliosides account for 80-90% of the total lipid-bound NeuAc content. The most striking change in the ganglioside pattern was the gradual increase in G3.

Animals↗
PubMed1992

Glycosylation pathways in the biosynthesis of gangliosides in melanoma and neuroblastoma cells: relative glycosyltransferase levels determine ganglioside patterns.

In order to elucidate some of the factors that determine the characteristic expression of gangliosides in malignant melanoma and neuroblastoma the levels of ganglioside synthases (glycosyltransferases) were determined in a panel of cell lines from those tumors that exhibited a wide range of ganglioside composition. Sialyltransferases (GM3, GD3, GD1a, and GT1b synthases), N-acetylgalactosaminyltransferases (GM2 and GD2 synthases), and galactosyltransferase (GM1 and GD1b synthases) were analyzed in crude membrane preparations from these cells. The results confirmed the importance of GM3 and GD3 synthases in determining the prominence of the a (GM3 to GT1a) or b (GD3 to GQ1b) biosynthetic pathways. The overall ganglioside composition in cells was found to be dependent on the relative levels of specific enzymes acting sequentially or in competing pathways. In general, the pattern and levels of transferases correlated with the actual ganglioside content of the cell line, although several important discrepancies were noted. For example, in cell lines containing high amounts of GD2 ganglioside, the level of the preceding enzyme in the pathway (GD3 synthase) was unexpectedly low. Thus, the high GD2:GD3 ratios characteristic of most neuroblastomas result from low levels of GD3 synthase as well as high levels of GD2 synthase. In other cell lines, GD3 synthase was completely absent, resulting in the synthesis of GM2, but not GD2, by N-acetylgalactosaminyltransferase I, as would be expected. It was concluded that different glycosyltransferases play key roles in determining glycolipid expression in different cell types.

Animals↗
PubMed1979

Isolation and characterization of gangliosides with a new sialosyl linkage and core structures. II. Gangliosides of human erythrocyte membranes.

Eight monosialosylgangliosides, G1 to G8, have been isolated from human erythrocyte membranes and their structures have been determined. Gangliosides G4 and G7 have been characterized by having 2 leads to 6-linked sialic acid to galactose at their termini. Ganglioside G5 was a positional isomer of a brain ganglioside GM1 as to the linkage of sialic acid. Ganglioside G8 was characterized as a branched chain ganglioside similar to a fucoganglioside previously isolated but devoid of fucose, and it showed a strong blood group I activity. Structures of these four new gangliosides are shown below: (formula: see text).

Carbohydrates↗