Essential roles of integrin-mediated signaling for the enhancement of malignant properties of melanomas based on the expression of GD3

Ohkawa, Yuki; Miyazaki, Sayaka; Miyata, Maiko; Hamamura, Kazunori; Furukawa, Koichi

doi:10.1016/j.bbrc.2008.05.149

Cited by 28 publications

(28 citation statements)

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“…(34) Recent progress in the isolation and manipulation of glycosyltransferase cDNA enabled us to investigate the roles of these gangliosides in cancer phenotypes. (35) Since we cloned cDNA of GD3 synthase, (13) we have investigated roles of GD3 synthase in melanomas (25,27,31,36,37) and in small-cell lung carcinomas. (38,39) Consequently, it has been demonstrated that the melanoma-specific ganglioside GD3 plays crucial roles in increased proliferation, enhanced invasion and cell adhesion in melanoma cells.…”

Section: Discussionmentioning

confidence: 99%

Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides

Miyata¹,

Kambe²,

Tajima³

et al. 2011

Cancer Science

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NEU3 is a membrane sialidase specific for gangliosides. Its increased expression and implication in some cancers have been reported. Here, we analyzed NEU3 expression in malignant melanoma cell lines and its roles in the cancer phenotypes. Quantitative RT-PCR revealed that high levels of the NEU3 gene were expressed at almost equivalent levels with those in colon cancers. To examine the effects of overexpression of NEU3, NEU3 cDNA-transfectant cells were established using a melanoma cell line SK-MEL-28 and its mutant N1 lacking GD3. SK-MEL-28 sublines overexpressing both the NEU3 gene and NEU3 enzyme activity showed no changes in both cell growth and ganglioside expression, while N1 cells showed a mild increase in cell proliferation with increased phosphorylation of the EGF receptor and neo-synthesis of Gb3 after NEU3 transfection. In contrast, NEU3 silencing resulted in a definite reduction in cell growth in a melanoma line MeWo, while ganglioside patterns underwent minimal changes. Phosphorylation levels of ERK1 ⁄ 2 with serum stimulation decreased in the NEU3-silenced cells. All these results suggest that NEU3 is highly expressed to enhance malignant phenotypes including apoptosis inhibition in malignant melanomas. (Cancer Sci 2011; 102: 2139-2149

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Section: Discussionmentioning

confidence: 99%

Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides

Miyata¹,

Kambe²,

Tajima³

et al. 2011

Cancer Science

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“…In recent years, GD3 has emerged as a cell death effector because of its role in apoptosis signaling in different cellular types by inducing mitochondrial damage (34,35). However, GD3 has also been reported to be overexpressed in a variety of tumors, especially in melanomas, where GD3 promotes tyrosine phosphorylation of paxillin, thereby resulting in an increased cell growth and an increased invasion by adhesion signals via integrin (36,37). Recently, it was also suggested that the signal transduction in ganglioside GD3-enriched lipid microdomains is involved in the growth cone morphology of cerebellar granule cells (38).…”

Section: Discussionmentioning

confidence: 99%

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Vilcaes¹,

Demichelis²,

Daniotti³

2011

Journal of Biological Chemistry

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Gangliosides are acidic glycosphingolipids that contain sialic acid residues and are expressed in nearly all vertebrate cells. They are synthesized at the Golgi complex by a combination of glycosyltransferase activities followed by vesicular delivery to the plasma membrane, where they participate in a variety of physiological as well as pathological processes. Recently, a number of enzymes of ganglioside anabolism and catabolism have been shown to be associated with the plasma membrane. In particular, it was observed that CMP-NeuAc:GM3 sialyltransferase (Sial-T2) is able to sialylate GM3 at the plasma membrane (ciscatalytic activity). In this work, we demonstrated that plasma membrane-integrated ecto-Sial-T2 also displays a trans-catalytic activity at the cell surface of epithelial and melanoma cells. By using a highly sensitive enzyme-linked immunosorbent assay combined with confocal fluorescence microscopy, we observed that ecto-Sial-T2 was able to sialylate hydrophobically or covalently immobilized GM3 onto a solid surface. More interestingly, we observed that ecto-Sial-T2 was able to sialylate GM3 exposed on the membrane of neighboring cells by using both the exogenous and endogenous donor substrate (CMP-N-acetylneuraminic acid) available at the extracellular milieu. In addition, the trans-activity of ecto-Sial-T2 was considerably reduced when the expression of the acceptor substrate was inhibited by using a specific inhibitor of biosynthesis of glycolipids, indicating the lipidic nature of the acceptor. Our findings provide the first direct evidence that an ecto-sialyltransferase is able to trans-sialylate substrates exposed in the plasma membrane from mammalian cells, which represents a novel insight into the molecular events that regulate the local glycosphingolipid composition.Glycosphingolipids are amphipathic molecules consisting of a ceramide lipid moiety linked to a glycan chain of variable length and structure. Among these are found gangliosides, which are sialosylated glycosphingolipids mainly located in the outer layer of the plasma membrane of vertebrate cells (1, 2) and have been implicated in many physiological processes, including growth, differentiation, migration and apoptosis through modulating both cell signaling processes and cell-tocell and cell-to-matrix interactions (3-6). Furthermore, gangliosides have been associated with a wide range of pathological processes, being receptors for both viruses and antibodies (7,8).The biosynthesis of gangliosides is mainly carried out in the lumen of the Golgi cisternae by a complex system of membrane-bound glycolipid acceptors, nucleotide sugar donors, glycosyltransferases, and nucleotide sugar transporters (1, 9). These neosynthesized gangliosides move through the Golgi complex to the plasma membrane via the lumenal surface of transport vesicles (10 -12). It is very well documented that glycosphingolipid expression, including gangliosides, is mainly regulated at the transcriptional and posttranscriptional levels of glycolipid glycosyltransferases a...

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“…Expression of GD3 apparently enhanced cell attachment to the extracellular matrix and increased phosphorylation levels of adaptor molecules during adhesion (13). These results suggested that signals mediated via growth factor receptor(s) and those mediated via adhesion receptor integrins might converge in the vicinity of the cell membrane.…”

mentioning

confidence: 88%

“…Furthermore, the effects of GD3 on cell adhesion were analyzed (13). Expression of GD3 apparently enhanced cell attachment to the extracellular matrix and increased phosphorylation levels of adaptor molecules during adhesion (13).…”

mentioning

confidence: 99%

Functional Activation of Src Family Kinase Yes Protein Is Essential for the Enhanced Malignant Properties of Human Melanoma Cells Expressing Ganglioside GD3

Hamamura¹,

Tsuji²,

Hara

et al. 2011

Journal of Biological Chemistry

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The possible roles of Src family kinases in the enhanced malignant properties of melanomas related to GD3 expression were analyzed. Among Src family kinases only Yes, not Fyn or Src, was functionally involved in the increased cell proliferation and invasion of GD3-expressing transfectant cells (GD3؉). Yes was located upstream of p130Cas and paxillin and at an equivalent level to focal adhesion kinase. Yes underwent autophosphorylation even before serum treatment and showed stronger kinase activity in GD3؉ cells than in GD3؊ cells following serum treatment. Coimmunoprecipitation experiments revealed that Yes bound to focal adhesion kinase or p130Cas more strongly in GD3؉ cells than in GD3؊ cells. As a possible mechanism for the enhancing effects of GD3 on cellular phenotypes, it was shown that majority of Yes was localized in glycolipidenriched microdomain/rafts in GD3؉ cells even before serum treatment, whereas it was scarcely detected in glycolipid-enriched microdomain/rafts in GD3؊ cells. An in vitro kinase assay of Yes revealed that coexistence of GD3 with Yes in membranous environments enhances the kinase activity of GD3؊ cell-derived Yes toward enolase, p125, and Yes itself. Knockdown of GD3 synthase resulted in the alleviation of tumor phenotypes and reduced activation levels of Yes. Taken together, these results suggest a role of GD3 in the regulation of Src family kinases.

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Essential roles of integrin-mediated signaling for the enhancement of malignant properties of melanomas based on the expression of GD3

Cited by 28 publications

References 20 publications

Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides

Membrane sialidase NEU3 is highly expressed in human melanoma cells promoting cell growth with minimal changes in the composition of gangliosides

Trans-activity of Plasma Membrane-associated Ganglioside Sialyltransferase in Mammalian Cells

Functional Activation of Src Family Kinase Yes Protein Is Essential for the Enhanced Malignant Properties of Human Melanoma Cells Expressing Ganglioside GD3

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