Diversity in cell surface sialic acid presentations: implications for biology and disease

Varki, Nissi; Varki, Ajit

doi:10.1038/labinvest.3700656

Cited by 460 publications

(419 citation statements)

References 51 publications

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“…The molecular mechanisms remain unclear, but action of transcription factors including hypoxia-inducible factor-1 may be indirectly involved. We surveyed possible transcription factors in the upstream region of the NEU4 gene using TF search 3 and found a transcription factor, P300, to be downregulated in colon cancer. The gene has also been identified as a co-activator of hypoxia-inducible factor-1␣ and a stimulating factor of hypoxia-induced genes (44), although we did not estimate the functional transcriptional activity of the gene in the cells used here.…”

Section: Discussionmentioning

confidence: 99%

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Regulation of Sialyl Lewis Antigen Expression in Colon Cancer Cells by Sialidase NEU4

Shiozaki

Yamaguchi

Takahashi

et al. 2011

Journal of Biological Chemistry

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Sialyl Lewis antigens, sialyl Lewis a and sialyl Lewis x, are utilized as tumor markers, and their increase in cancer is associated with tumor progression by enhancement of cancer cell adhesion to endothelial E-selectin. However, regulation mechanisms are not fully understood. We previously demonstrated that NEU4 is the only sialidase efficiently acting on mucins and it is downregulated in colon cancer. To elucidate the significance of NEU4 down-regulation, we investigated sialyl Lewis antigens as endogenous substrates for the sialidase. NEU4 was found to hydrolyze the antigens in vitro and decrease cell surface levels much more effectively than other sialidases. Western blot, thin layer chromatography, and metabolic inhibition studies of desialylation products revealed NEU4 to preferentially catalyze sialyl Lewis antigens expressed on O-glycans. Cell adhesion to and motility and growth on E-selectin were significantly reduced by NEU4. E-selectin stimulation of colon cancer cells enhanced cell motility through activation of the p38/Hsp27/actin reorganization pathway, whereas NEU4 attenuated the signaling. On immunocytochemical analysis, some NEU4 molecules were localized at cell surfaces. Under hypoxia conditions whereby the antigens were increased concomitantly with several sialyl-and fucosyltransferases, NEU4 expression was markedly decreased. These results suggest that NEU4 plays an important role in control of sialyl Lewis antigen expression and its impairment in colon cancer.

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Section: Discussionmentioning

confidence: 99%

“…Aberrant glycosylation is a characteristic feature of cancer cells, and especially alteration in sialylation during malignant transformation has been proposed to be associated with the malignant phenotype, including metastatic potential and invasiveness (1)(2)(3). Sialic acids, in fact, often include tumor-specific carbohydrates as tumor markers.…”

mentioning

confidence: 99%

Regulation of Sialyl Lewis Antigen Expression in Colon Cancer Cells by Sialidase NEU4

Shiozaki

Yamaguchi

Takahashi

et al. 2011

Journal of Biological Chemistry

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“…Sialic acids are present as terminal monosaccharides linked to cell surface glycoconjugates and play roles in a variety of physiological and pathological events (1). They are often a part of recognition sites for extrinsic pathogens (2), but they also play important roles by interacting with many intrinsic molecules, endogenous lectins.…”

mentioning

confidence: 99%

Binding of a Sialic Acid-recognizing Lectin Siglec-9 Modulates Adhesion Dynamics of Cancer Cells via Calpain-mediated Protein Degradation

Sabit

Hashimoto

Matsumoto

et al. 2013

Journal of Biological Chemistry

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Background: Siglec-9 binds sialylglycoconjugates on target cells probably causing signals in both sides of cells. Results: Co-culture with Siglec-9-expressing U937 caused degradation of focal adhesion kinase and related proteins in an astrocytoma cell line. Conclusion: Interaction between Siglec-9 and its counterreceptor triggered activation signals in cancer cells via calpain. Significance: Cancer cells may utilize sialylglycoconjugates recognized by Siglec-9 to escape from immunosurveillance.

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“…[13][14][15] Alterations in glycosylation occur during tumorigenesis, and aberrant sialylation in particular has been implicated in the malignant phenotype with reference to metastatic potential and invasiveness. [16][17][18] Mammalian sialidase is the key enzyme for control of cellular sialic acid contents, through catalyzing the initial step in degradation of glycoproteins and glycolipids. Four types of human sialidases have been identified and characterized to date, designated as NEU1, NEU2, NEU3 and NEU4.…”

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confidence: 99%

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

et al. 2011

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Prostate cancers generally become androgen-independent and resistant to hormone therapy with progression. To understand the underlying mechanisms and facilitate the development of novel treatments for androgen-independent prostate cancer, we have investigated plasma membrane-associated sialidase (NEU3), the key enzyme for ganglioside hydrolysis participating in transmembrane signaling. We have discovered NEU3 to be upregulated in human prostate cancer compared with non-cancerous tissue, correlating with the Gleason score. NEU3 silencing with siRNA in prostate cancer PC-3 and LNCaP cells resulted in increased expression of differentiation markers and in cell apoptosis, but decrease in Bcl-2 as well as a progression-related transcription factor, early growth response gene (EGR-1). In androgen-sensitive LNCaP cells, forced overexpression of NEU3 significantly induced expression of EGR-1, androgen receptor (AR) and PSA both with and without androgen, the cells becoming sensitive to androgen. The NEU3-mediated induction was abrogated by inhibitors for PI-3 kinase and MAP kinase and more specifically by their silencing in the absence of androgen, being confirmed by increased phosphorylation of AKT and ERK1/2 in NEU3 overexpressing cells. NEU3 siRNA introduction caused reduction of cell growth of an androgen-independent PC-3 cells in culture and of transplanted tumors in nude mice. These data suggest that NEU3 regulates tumor progression through AR signaling, and thus be a potential tool for diagnosis and therapy of androgen-independent prostate cancer.

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Diversity in cell surface sialic acid presentations: implications for biology and disease

Cited by 460 publications

References 51 publications

Regulation of Sialyl Lewis Antigen Expression in Colon Cancer Cells by Sialidase NEU4

Regulation of Sialyl Lewis Antigen Expression in Colon Cancer Cells by Sialidase NEU4

Binding of a Sialic Acid-recognizing Lectin Siglec-9 Modulates Adhesion Dynamics of Cancer Cells via Calpain-mediated Protein Degradation

Plasma membrane-associated sialidase (NEU3) regulates progression of prostate cancer to androgen-independent growth through modulation of androgen receptor signaling

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