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

Abstract

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

Human airway epithelia express catalytically active NEU3 sialidase

“…NEU3 physically and/or functionally interacts with caveolin-1 (67), Rac1 (68), integrins ␤1 (59) and ␤4 (26), Grb-2 (52), Akt (59), focal adhesion kinase (59), and Ras (62). NEU3 strongly regulates insulin (52,69) and EGFR (34,38,59,62,68) signaling pathways and alters expression of multiple metalloproteinases (MMPs), including MMP-2, MMP-7, and MMP-9 (24,29,43,59). In conclusion, this report demonstrates that human airway ECs express catalytically active NEU3 sialidase and implicate NEU3 in multiple biological processes within human airway epithelia.…”

“…The caveolin-binding sequence promotes NEU3 association with the scaffolding protein, caveolin-1, and its sequestration within microdomains in the plasma membrane (67), in close proximity to a variety of signaling elements (44). In fact, NEU3 influences signaling events coupled to multiple cell surface receptors (37), including the epidermal growth factor receptor (EGFR) (34,38,59,62,68), the insulin receptor (52,69), Toll-like receptor (TLR)4 (5), and the TrkA receptor (24). NEU3 differentially hydrolyzes SA residues in various gangliosides, exerting greater activity for GM3, GD1a, GD1b, and GD3 but far less, if any, activity for GM1 and GM2 (36,63).…”

Molecular subtyping of metastatic melanoma based on cell ganglioside metabolism profiles

“…In particular, the activation of GD3 synthase is linked to the increment of GD3 in melanoma cells [11, 20]. Similarly, the plasma membrane sialidase NEU3 has been shown to be highly expressed in human melanoma cell lines [21]. …”

NEU3 Sialidase Protein Interactors in the Plasma Membrane and in the Endosomes

“…In fact, the overexpression of the human ortholog NEU3 in a mouse model induces the development of insulin-resistant diabetes mellitus (11). Also, an excessive up-regulation of NEU3 has been detected in various neoplasms, including colon (12), renal (13,14), ovarian (15), melanoma (16), and prostate cancers (17), although a down-regulation of the enzyme has been observed in acute lymphoblastic leukemia (18).…”