Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025202 (melanoma)
 69,561 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Integrin alpha(5)beta(1), a major fibronectin receptor, functions in a wide variety of biological phenomena. We have found that alpha 2-8-linked oligosialic acids with 5 < or = degree of polymerization (DP) < or = 7 occur on integrin alpha(5) subunit of the human melanoma cell line G361. The integrin alpha(5) subunit immunoprecipitated with anti-integrin alpha(5) antibody reacted with the monoclonal antibody 12E3, which recognizes oligo/polysialic acid with DP > or = 5 but not with the polyclonal antibody H.46 recognizing oligo/polysialic acid with DP > or = 8. The occurrence of oligosialic acids was further demonstrated by fluorometric C(7)/C(9) analysis on the immunopurified integrin alpha(5) subunit. Oligosialic acids were also found in the alpha(5) subunit of several other human cells such as foreskin fibroblast and chronic erythroleukemia K562 cells. These results suggest the ubiquitous modification with unique oligosialic acids occurs on the alpha(5) subunit of integrin alpha(5)beta(1). The adhesion of human melanoma G361 cells to fibronectin was mainly mediated by integrin alpha(5)beta(1). Treatment of cells with sialidase from Arthrobacter ureafaciens cleaving alpha 2-3-, alpha 2-6-, and alpha 2-8-linked sialic acids inhibited adhesion to fibronectin. On the other hand, N-acetylneuraminidase II, which cleaves alpha 2-3 and alpha 2-6 but not alpha 2-8 linkages, showed no inhibitory activity. After the loss of oligosialic acids, integrin alpha(5)beta(1) failed to bind to fibronectin-conjugated Sepharose, indicating that the oligosialic acid on the alpha(5) subunit of integrin alpha(5)beta(1) plays important roles in cell adhesion to fibronectin.
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PMID:Occurrence of oligosialic acids on integrin alpha 5 subunit and their involvement in cell adhesion to fibronectin. 1141 85

Siglec-7 is a sialic acid binding receptor with inhibitory potential, expressed on human NK cells and monocytes. It has an unusual binding preference for alpha2,8-linked disialic acids, such as those displayed by ganglioside GD3. Here we have investigated whether siglec-7-GD3 interactions are able to modulate NK cell cytotoxicity. Using synthetic polyacrylamide glycoprobes, siglec-7 was found to be masked at the NK cell surface but it could be unmasked by sialidase treatment of NK cells. GD3 synthase-transfected P815 target cells expressed high levels of GD3 and bound strongly to recombinant siglec-7-Fc protein. Surprisingly, GD3 synthase-transfected P815 cells were killed more effectively by untreated cells in a siglec-7-independent manner. However, following sialidase treatment of NK cells, a siglec-7-dependent inhibition of killing was observed. These findings have important implications for NK cell cytotoxicity against tumor cells like melanoma that express high levels of GD3 ganglioside.
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PMID:Ganglioside GD3 expression on target cells can modulate NK cell cytotoxicity via siglec-7-dependent and -independent mechanisms. 1277 82

Newcastle disease virus (NDV) is an avian paramyxovirus with replication competence in human tumor cells and interesting anti-neoplastic and immune stimulatory properties. In order to increase tumor selectivity of replication, we prepared mutants from the avirulent strain Ulster with monocyclic replication cycle and adapted them for multicyclic replication in human melanoma cells. Two mutants (M1 and M2) showed interesting functional differences: while M2 showed T cell co-stimulatory effects in a tumor-specific cytotoxic T lymphocyte (CTL) assay, M1 did not. A distinct difference of these 2 virus mutants appeared also when testing their capacity to induce interferon-alpha and -beta as well as tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) molecules in human monocytes. Sequence analysis of the hemagglutinin-neuraminidase (HN) molecules of the 2 virus mutants showed 7 non-silent mutational differences. Upon cloning of the HN mutant genes into an expression vector and transfection of cells, only HN derived from M2 (HN-M2) was detected at the cell surface by immunostaining with specific antibodies and showed hemadsorption and neuraminidase activity. In order to define which amino acid was responsible for the loss of functional activity of HN derived from M1 (HN-M1), distinct HN mutants were generated via site-directed mutagenesis and tested. Substitution of serine 200 by a proline abrogated HN expression and its hemadsorption and neuraminidase activities. Molecular modeling revealed that proline 200 in HN influences flexibility of a loop near the entrance to the neuraminidase active site, a function that may be crucial for the functions of this viral protein.
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PMID:Importance of serine 200 for functional activities of the hemagglutinin-neuraminidase protein of Newcastle Disease Virus. 1476 47

Previous studies have shown a statistically significant correlation between human carcinomas and monoclonal antibody detection of a Mycoplasma hyorhinis-encoded protein known as p37. A potential mechanism of p37 is that it might promote invasion and metastasis. Recombinant p37 enhanced the invasiveness of two prostate carcinoma and two melanoma cell lines in a dose-dependent manner in vitro, but did not have a significant effect on tumor cell growth. Furthermore, the increased binding to cell surfaces and the enhanced invasive potential of cancer cells from exposure to p37 could be completely reversed by preincubation of the cancer cells with an anti-p37 monoclonal antibody. Sequence comparisons, followed by three-dimensional molecular modeling, revealed a region of similarity between p37 and influenza hemagglutinin A, a sialic acid-binding protein that plays a critical role in viral entry. Binding of p37 to prostate carcinoma cells was found to be at least partially sialic acid dependent because neuraminidase treatment decreased this binding. Taken together, these observations suggest that M. hyorhinis can infect humans and may facilitate tumor invasiveness via p37. These results further suggest that p37 may be a molecular target for cancer therapy.
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PMID:p37 Induces tumor invasiveness. 1602 Jun 60

Drusen are a marker of age-related macular degeneration (AMD). Lesions similar to drusen, both in histology and their clinical appearance, are also seen in choroidal tumours, chronic inflammatory and degenerative conditions of the eye, and in mesangiocapillary glomerulonephritis type II (MCGN-II). This study aims to compare the saccharide composition of these drusen-like lesions in the various ocular pathological groups and in MCGN-II. Formalin fixed and paraffin wax embedded tissue from 21 eyes was studied. The histological diagnoses included AMD, retinal detachment, phthisis bulbi following failed retinal detachment surgery, malignant melanoma, long-standing uveitis, glaucoma and MCGN II. Glycosylation was examined using a panel of twenty biotinylated lectins and an avidin-peroxidase DAB-cobalt revealing system, with and without neuraminidase pre-treatment. High mannose, bi/tri-nonbisected and bisected complex N-glycan, N-acetyl glucosaminyl, galactosyl and sialyl residues were found to be expressed by drusen, while treatment with neuraminidase exposed subterminal N-acetyl galactosamine and galactosyl residues. Similar binding patterns were found in the various pathological groups studied. As there was no significant difference in the lectin-binding pattern in drusen in different pathologies, a common pathogenesis or at least a final common pathway for the elaboration of carbohydrate components of drusen is suggested.
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PMID:Glycoproteins of drusen and drusen-like lesions. 1784 3

The avian paramyxovirus Newcastle disease virus (NDV) selectively replicates in tumor cells and is known to stimulate T-cell-, macrophage-, and NK cell-mediated responses. The mechanisms of NK cell activation by NDV are poorly understood so far. We studied the expression of ligand structures for activating NK cell receptors on NDV-infected tumor cells. Upon infection with the nonlytic NDV strain Ulster and the lytic strain MTH-68/H, human carcinoma and melanoma cells showed enhanced expression of ligands for the natural cytotoxicity receptors NKp44 and NKp46, but not NKp30. Ligands for the activating receptor NKG2D were partially downregulated. Soluble NKp44-Fc and NKp46-Fc, but not NKp30-Fc, chimeric proteins bound specifically to NDV-infected tumor cells and to NDV particle-coated plates. Hemagglutinin-neuraminidase (HN) of the virus serves as a ligand structure for NKp44 and NKp46, as indicated by the blockade of binding to NDV-infected cells and viral particles in the presence of anti-HN antibodies and by binding to cells transfected with HN cDNA. Consistent with the recognition of sialic acid moieties by the viral lectin HN, the binding of NKp44-Fc and NKp46-Fc was lost after desialylation. NKp44- and NKp46-CD3zeta lacZ-inducible reporter cells were activated by NDV-infected cells. NDV-infected tumor cells stimulated NK cells to produce increased amounts of the effector lymphokines gamma interferon and tumor necrosis factor alpha. Primary NK cells and the NK line NK-92 lysed NDV-infected tumor cells with enhanced efficiency, an effect that was eliminated by the treatment of target cells with the neuraminidase inhibitor Neu5Ac2en. These results suggest that direct activation of NK cells contributes to the antitumor effects of NDV.
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PMID:Activation of natural killer cells by newcastle disease virus hemagglutinin-neuraminidase. 1951 83

The essential toxin in Clostridium perfringens-mediated gas gangrene or clostridial myonecrosis is alpha-toxin, although other toxins and extracellular enzymes may also be involved. In many bacterial pathogens extracellular sialidases are important virulence factors, and it has been suggested that sialidases may play a role in gas gangrene. C. perfringens strains have combinations of three different sialidase genes, two of which, nanI and nanJ, encode secreted sialidases. The nanI and nanJ genes were insertionally inactivated by homologous recombination in derivatives of sequenced strain 13 and were shown to encode two functional secreted sialidases, NanI and NanJ. Analysis of these derivatives showed that NanI was the major sialidase in this organism. Mutation of nanI resulted in loss of most of the secreted sialidase activity, and the residual activity was eliminated by subsequent mutation of the nanJ gene. Only a slight reduction in the total sialidase activity was observed in a nanJ mutant. Cytotoxicity assays using the B16 melanoma cell line showed that supernatants containing NanI or overexpressing NanJ enhanced alpha-toxin-mediated cytotoxicity. Finally, the ability of nanI, nanJ, and nanIJ mutants to cause disease was assessed in a mouse myonecrosis model. No attenuation of virulence was observed for any of these strains, providing evidence that neither the NanI sialidase nor the NanJ sialidase is essential for virulence.
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PMID:The NanI and NanJ sialidases of Clostridium perfringens are not essential for virulence. 1965 73

We have previously shown that Wnt5A-mediated signaling can promote melanoma metastasis. It has been shown that Wnt signaling is antagonized by the protein Klotho, which has been implicated in aging. We show here that in melanoma cells, expressions of Wnt5A and Klotho are inversely correlated. In the presence of recombinant Klotho (rKlotho), we show that Wnt5A internalization and signaling is decreased in high Wnt5A-expressing cells. Moreover, in the presence of rKlotho, we observe an increase in Wnt5A remaining in the medium, coincident with an increase in sialidase activity, and decrease in syndecan expression. These effects can be inhibited using a sialidase inhibitor. In addition to its effects on Wnt5A internalization, we also demonstrate that Klotho decreases melanoma cell invasive potential by a second mechanism that involves the inhibition of calpain and a resultant decrease in filamin cleavage, which we demonstrate is critical for melanoma cell motility.
Pigment Cell Melanoma Res 2011 Feb
PMID:Loss of Klotho during melanoma progression leads to increased filamin cleavage, increased Wnt5A expression, and enhanced melanoma cell motility. 2095 50

Tumor cell (TC) metastasis is initiated by selective adhesion of TCs to target structures such as basement membrane and endotheliaI cells (ECs), followed by transvascular migration of TCs. Variants of murine B16 melanoma having different metastatic potentials (in the order BL6 greater than or equal to F10>F1>WA4) have been characterized by the same decreasing order of cell surface G(M3) expression level, relative adhesiveness to nonactivated ECs, and relative degree of G(M3)-dependent adhesion to Gg3Cer- or LacCer-coated plates. Degree of integrin-dependent cell adhesion and adhesion to IL-1-activated ECs was similar for BL6, F10, and F1. These results suggest that metastatic potential of these B16 variants is closely dependent on relative adhesion to nonactivated ECs, which is based on G(M3)-Gg3Cer or G(M3)-LacCer interaction. This possibility has been supported by further studies showing that blocking of G(M3)-dependent melanoma adhesion by mu M-order concentrations of G(M3) or Gg3Cer in liposomes, or by sialidase treatment of melanoma cells, strongly inhibited BL6 metastasis to lung. Paragloboside or sialylparagloboside did not affect G(M3)-dependent BL6 cell adhesion and did not inhibit metastasis. Spontaneous metastasis from subcutaneously-grown tumors was significantly reduced if G(M3)- or Gg3Cer-liposomes were intravenously injected during tumor growth. Thus, blocking of TC adhesion to nonactivated ECs based on carbohydrate-carbohydrate interaction may provide effective anti-adhesion therapy against tumor progression, in analogy to the antimetastatic effect produced by blocking of integrin-dependent cell adhesion.
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PMID:Inhibition of b16 melanoma metastasis by administration of g(m3)- or gg3- liposomes - blocking adhesion of melanoma-cells to endothelial-cells (antiadhesion therapy) via inhibition of g(m3)-gg3cer or g(m3)-laccer interaction. 2155 40

Loss of endothelial adherens junctions is involved in tumor metastasis. Here, we demonstrate that, in the metastatic Lu1205 melanoma cells, expression of the CD44 variant CD44v8-v10 induced junction disassembly and vascular endothelial (VE)-cadherin phosphorylation at Y658 and Y731. Short interfering RNA (siRNA)-mediated CD44 knockdown or sialic acid cleavage reversed these effects. Moreover, microspheres coated with recombinant CD44v8-v10 promoted endothelial junction disruption. Overexpression of CD44v8-v10 but not of standard CD44 (CD44s) promoted gap formation in the non-metastatic WM35 melanoma cells, whereas CD44 knockdown or neuraminidase treatment dramatically diminished melanoma transendothelial migration. Endothelial cells transfected with the phosphomimetic VE-cadherin mutant Y658E supported transmigration of CD44-silenced Lu1205 cells. Our findings imply that CD44 variant isoform (CD44v) but not CD44s regulates endothelial junction loss, promoting melanoma extravasation.
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PMID:CD44 variant, but not standard CD44 isoforms, mediate disassembly of endothelial VE-cadherin junction on metastatic melanoma cells. 2567 36


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