Relations of the type and branch of surface N-glycans to cell adhesion, migration and integrin expressions

Zhang, Ying; Zhao, Jiahong; Zhang, Xia-Ying; Guo, Hua-Bei; Liu, Fei; Chen, Huili

doi:10.1023/b:mcbi.0000026065.84798.62

Cited by 38 publications

(36 citation statements)

References 29 publications

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“…Likewise, siRNA knockdown of GlcNAc-TV in malignant cells impairs cell migration and invasion (28). Although digoxin's inhibition of cell migration and invasion are consistent with its effects on the N-glycan remodeling, we cannot exclude that these effects are related to other pathways effected by the molecule.…”

Section: Discussionmentioning

confidence: 83%

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Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

et al. 2008

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Aberrant N-linked glycans promote the malignant potential of cells by enhancing the epithelial-to-mesenchymal transition and the invasive phenotype. To identify small molecule inhibitors of N-glycan biosynthesis, we developed a chemical screen based on the ability of the tetravalent plant lectin L-phytohemagglutinin (L-PHA) to bind and crosslink surface glycoproteins with B1,6GlcNAc-branched complex type N-glycans and thereby induce agglutination and cell death. In this screen, Jurkat cells were treated with a library of offpatent chemicals (n = 1,280) to identify molecules that blocked L-PHA-induced death. The most potent hit from this screen was the cardiac glycoside (CG) dihydroouabain. In secondary assays, a panel of CGs was tested for their effects on L-PHAinduced agglutination and cell death. All of the CGs tested inhibited L-PHA-induced death in Jurkat cells, and the most potent CG tested was digoxin with an EC 50 of 60 F 20 nmol/L. Digoxin also increased the fraction of some concanavalin A-binding N-glycans. Using matrix-assisted laser desorption/ionization time-of-flight mass spectrometry, digoxin specifically increased GlcNAc 1 Man 3 GlcNAc 2 Fuc 1 and GlcNAc 2 Man 3 GlcNAc 2 Fuc 1 oligosaccharides demonstrating an impairment of the N-glycan pathway. Consistent with this effect on the N-glycan pathway, digoxin inhibited N-glycosylation-mediated processes of tumor cell migration and invasion. Furthermore, digoxin prevented distant tumor formation in two mouse models of metastatic prostate cancer. Thus, taken together, our high throughput screen identified CGs as modifiers of the N-glycan pathway. These molecules can be used as tools to better understand the role of N-glycans in normal and malignant cells. Moreover, these results may partly explain the anticancer effect of CGs in cardiovascular patients. [Cancer Res 2008;68(16):6688-97]

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Section: Discussionmentioning

confidence: 83%

“…Increased GlcNAc branching of N-glycans on the cell surface promotes the malignant and metastatic potential of cells by altering cell migration and invasion (1,28). As treatment with digoxin altered the N-glycan remodeling, we evaluated the effects of this compound on the N-glycosylation-mediated processes of cell migration and invasion.…”

Section: Resultsmentioning

confidence: 99%

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

et al. 2008

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“…To confirm that the inhibitory effect of GM3 on EGF-induced P-EGFR is due to interaction of N-linked glycan of EGFR having GlcNAc termini with GM3 surrounding the receptor, the effect of modification of N-linked glycan processing (24) was examined. Swainsonine (SW), which inhibits ␣-mannosidase-II, caused accumulation of hybrid-type (25) having GlcNAc termini with a high level of GS-II binding sites (Fig. 4A) and enhanced the GM3-dependent inhibitory effect on EGF-induced EGFR kinase activity in situ using cells in culture (Fig.…”

Section: Interaction Of Gm3 and Other Gsls With Egfr And Inhibition mentioning

confidence: 99%

Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor

Yoon

Nakayama²,

Hikita

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

193

127

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Epidermal growth factor receptor (EGFR) at membrane microdomains plays an essential role in the growth control of epidermal cells, including cancer cells derived therefrom. Ligand-dependent activation of EGFR tyrosine kinase is known to be inhibited by ganglioside GM3, but to a much lesser degree by other glycosphingolipids. However, the mechanism of the inhibitory effect of GM3 on EGFR tyrosine kinase has been ambiguous. The mechanism is now defined by binding of N-linked glycan having multiple GlcNAc termini to GM3 through carbohydrate-to-carbohydrate interaction, based on the following data: (i) EGFR (molecular mass, Ϸ170 kDa) has N-linked glycan with GlcNAc termini, as probed by mAb (J1) or lectin (GS-II); (ii) GS-II-bound EGFR also bound to anti-EGFR Ab as well as to GM3-coated beads; (iii) GM3 inhibitory effect on EGFR tyrosine kinase was abrogated in vitro by coincubation with glycan having multiple GlcNAc termini and in cell culture in situ incubated with the same glycan; and (iv) cells treated with swainsonine, which increased expression of complex-type and hybridtype glycans with GlcNAc termini, displayed higher inhibition of EGFR kinase by GM3 than swainsonine-untreated control cells. A similar effect was observed with 1-deoxymannojirimycin, which increased hybrid-type structure in addition to major accumulation of high mannose-type glycan. These findings indicate that N-linked glycan with GlcNAc termini linked to EGFR is the target to interact with GM3, causing inhibition of EGF-induced EGFR tyrosine kinase.carbohydrate-to-carbohydrate interaction ͉ N-linked glycan ͉ glycosphingolipid ͉ ganglioside ͉ oligosaccharide Fr.B

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“…SW functions as an α‐mannosidase II inhibitor and can efficiently decrease tumor size in nude mice injected with leukemic cells 14, 15. DMJ functions as an α‐mannosidase I inhibitor, which induces apoptosis and decreases the migration ability16 of hepatocarcinoma cells 17. MAN1B1 has also been reported to promote hepatocellular carcinoma (HCC) formation 18.…”

Section: Introductionmentioning

confidence: 99%

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

Hsiao

Yang

et al. 2017

Hepatology Communications

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α‐1,2 mannosidases, key enzymes in N‐glycosylation, are required for the formation of mature glycoproteins in eukaryotes. Aberrant regulation of α‐1,2 mannosidases can result in cancer, although the underlying mechanisms are unclear. Here, we report the distinct roles of α‐1,2 mannosidase subtypes (MAN1A, MAN1B, ERMAN1, MAN1C) in the formation of hepatocellular carcinoma (HCC). Clinicopathological analyses revealed that the clinical stage, tumor size, α‐fetoprotein level, and invasion status were positively correlated with the expression levels of MAN1A1, MAN1B1, and MAN1A2. In contrast, the expression of MAN1C1 was decreased as early as stage I of HCC. Survival analyses showed that high MAN1A1, MAN1A2, and MAN1B1 expression levels combined with low MAN1C1 expression levels were significantly correlated with shorter overall survival rates. Functionally, the overexpression of MAN1A1 promoted proliferation, migration, and transformation as well as in vivo migration in zebrafish. Conversely, overexpression of MAN1C1 reduced the migration ability both in vitro and in vivo, decreased the colony formation ability, and shortened the S phase of the cell cycle. Furthermore, the expression of genes involved in cell cycle/proliferation and migration was increased in MAN1A1‐overexpressing cells but decreased in MAN1C1‐overexpressing cells. MAN1A1 activated the expression of key regulators of the unfolded protein response (UPR), while treatment with endoplasmic reticulum stress inhibitors blocked the expression of MAN1A1‐activated genes. Using the MAN1A1 liver‐specific overexpression zebrafish model, we observed steatosis and inflammation at earlier stages and HCC formation at a later stage accompanied by the increased expression of the UPR modulator binding immunoglobulin protein (BiP). These data suggest that the up‐regulation of MAN1A1 activates the UPR and might initiate metastasis. Conclusion: MAN1A1 represents a novel oncogene while MAN1C1 plays a role in tumor suppression in hepatocarcinogenesis. (Hepatology Communications 2017;1:230‐247)

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Relations of the type and branch of surface N-glycans to cell adhesion, migration and integrin expressions

Cited by 38 publications

References 29 publications

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

Inhibition of the Sodium/Potassium ATPase Impairs N-Glycan Expression and Function

Epidermal growth factor receptor tyrosine kinase is modulated by GM3 interaction with N-linked GlcNAc termini of the receptor

Up‐regulation of golgi α‐mannosidase IA and down‐regulation of golgi α‐mannosidase IC activates unfolded protein response during hepatocarcinogenesis

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