O-Glycan inhibitors generate aryl-glycans, induce apoptosis and lead to growth inhibition in colorectal cancer cell lines

Patsos, Georgios; Hebbe-Viton, V; Robbe-Masselot, Catherine; Masselot, David; Martin, Raul San; Greenwood, Rosemary; Paraskeva, Christos; Klein, Andreas; Graessmann, M.; Michalski, Jean Claude; Gallagher, Timothy; Corfield, Anthony P.

doi:10.1093/glycob/cwn149

Cited by 38 publications

(37 citation statements)

References 48 publications

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“…45 The roles of O-linked glycans and mucins in cell differentiation, regulation of cell growth through apoptosis, and proliferation have been extensively studied. 46,122 O-glycosylation occurs frequently on secreted or membrane-bound mucins that are rich in serine and threonine. 133 Moreover, O-glycans, including Lewis antigens, are involved in the adhesion and invasion of cancer cells and are often altered and highly sialylated in cancer cells.…”

Section: Glycoprotein Glycosylation and Cancer Progressionmentioning

confidence: 99%

Glycomechanics of the Metastatic Cascade: Tumor Cell–Endothelial Cell Interactions in the Circulation

2011

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Hydrodynamic shear force plays an important role in the leukocyte adhesion cascade that involves the tethering and rolling of cells along the endothelial layer, their firm adhesion or arrest, and their extravasation or escape from the circulatory system by inducing passive deformation, or cell flattening, and microvilli stretching, as well as regulating the expression, distribution, and conformation of adhesion molecules on leukocytes and the endothelial layer. Similarly, the dissemination of circulating tumor cells (CTCs) from the primary tumor sites is believed to involve tethering, rolling, and firm adhesion steps before their eventual extravasation which leads to secondary tumor sites (metastasis). Of particular importance to both the leukocyte adhesion cascade and the extravasation of CTCs, glycoproteins are involved in all three steps (capture, rolling, and firm adhesion) and consist of a variety of important selectin ligands. This review article provides an overview of glycoprotein glycosylation associated with the abnormal glycan expression on cancer cell surfaces, where well-established and novel selectin ligands that are cancer related are discussed. An overview of computational approaches on the effects of fluid mechanical force on glycoprotein mediated cancer cell rolling and adhesion is presented with a highlight of recent flow-based and selectin-mediated cell capturing/enriching devices. Finally, as an important branch of the glycoprotein family, mucins, specifically MUC1, are discussed in the context of their aberrant expression on cancer cells and their role as cancer cell adhesion molecules. Since metastasis relies heavily on glycoprotein interactions in the bloodstream where the fluid shear stress highly regulates cell adhesion forces, it is important to study and understand the glycomechanics of all relevant glycoproteins (well-established and novel) as they relate to the metastatic cascade.

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Section: Glycoprotein Glycosylation and Cancer Progressionmentioning

confidence: 99%

Glycomechanics of the Metastatic Cascade: Tumor Cell–Endothelial Cell Interactions in the Circulation

2011

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“…We first used benzyl 2-acetamido-2-deoxy-α-D-galactopyranoside (BADG), an analog of GalNAc-α-1-O-serine/threonine that acts as a competitive inhibitor to O-glycan chain extension (15,16). Because some cell lines accumulate cytotoxic, nonphysiological arylglycans after many days of BADG treatment (17), we used shorter incubations and monitored for LAMP1 level increases that can indicate this type of accumulation (16,17).…”

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confidence: 99%

“…Because some cell lines accumulate cytotoxic, nonphysiological arylglycans after many days of BADG treatment (17), we used shorter incubations and monitored for LAMP1 level increases that can indicate this type of accumulation (16,17). BADG treatment altered the glycosylation of LAMP1 protein but did not affect its abundance, as monitored by immunoblot of NPC1-deficient, primary human fibroblasts (Fig.…”

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confidence: 99%

Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells

Deffieu

Lee

et al. 2015

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

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Lysosomes are lined with a glycocalyx that protects the limiting membrane from the action of degradative enzymes. We tested the hypothesis that Niemann-Pick type C 1 (NPC1) protein aids the transfer of low density lipoprotein-derived cholesterol across this glycocalyx. A prediction of this model is that cells will be less dependent upon NPC1 if their glycocalyx is decreased in density. Lysosome cholesterol content was significantly lower after treatment of NPC1-deficient human fibroblasts with benzyl-2-acetamido-2-deoxy-α-D-galactopyranoside, an inhibitor of O-linked glycosylation. Direct biochemical measurement of cholesterol showed that lysosomes purified from NPC1-deficient fibroblasts contained at least 30% less cholesterol when O-linked glycosylation was blocked. As an independent means to modify protein glycosylation, we used Chinese hamster ovary ldl-D cells defective in UDP-Gal/UDP-GalNAc 4-epimerase in which N-and O-linked glycosylation can be controlled. CRISPR generated, NPC1-deficient ldl-D cells supplemented with galactose accumulated more cholesterol than those in which sugar addition was blocked. In the absence of galactose supplementation, NPC1-deficient ldl-D cells also transported more cholesterol from lysosomes to the endoplasmic reticulum, as monitored by an increase in cholesteryl [ 14 C]-oleate levels. These experiments support a model in which NPC1 protein functions to transfer cholesterol past a lysosomal glycocalyx.L ow-density lipoprotein-derived cholesterol is delivered to cells by receptor-mediated endocytosis and transport to lysosomes. Within lysosomes, cholesterol esters are hydrolyzed and cholesterol is exported to the cytoplasm for cellular use (1). Cholesterol export requires two lysosomal glycoproteins: NPC1 and NPC2 (2, 3). Patients carrying homozygous mutations in either of these proteins present with Niemann-Pick type C (NPC) disease, a neurological disorder that is associated with massive accumulation of unesterified cholesterol and glycosphingolipids in lysosomes (2-4).NPC2 is a small, soluble, cholesterol binding protein that is thought to pick up cholesterol both from lipoprotein lipase and from the abundant, intralumenal membranes present within lysosomes (5, 6). NPC1 is a much larger glycoprotein that contains 13 transmembrane domains and three, relatively large, lumenally oriented domains (2). NPC1's first (N-terminal), luminal domain binds cholesterol directly (7,8); the second domain can bind NPC2 in a cholesterol-dependent manner and has been proposed to facilitate transfer of cholesterol from NPC2 onto NPC1's N-terminal domain (9).The requirement for NPC1 and NPC2 proteins for cholesterol export from lysosomes is somewhat enigmatic because cholesterol can generally partition freely into membrane bilayers (10). The limiting membrane of lysosomes is lined predominantly by densely packed, highly glycosylated, lysosomal membrane proteins; their oligosaccharides are thought to protect the phospholipid bilayer from hydrolytic destruction (11,12). This glycoprotein coat ...

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“…In neuroblastoma, S-type cells are more susceptible to apolipoprotein 2 ligand/tumor necrosis factor-related apoptosisinducing ligand (Apo2L/TRAIL)-mediated apoptosis than N-type cells, owing to their expression of caspase-8 (29 ). O-glycosylation pathways have been found to play a role in the regulation of cell growth by modifying the rate of apoptosis of cancer cells (37,38 ).…”

Section: Discussionmentioning

confidence: 99%

GALNT9 Gene Expression Is a Prognostic Marker in Neuroblastoma Patients

et al. 2013

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BACKGROUND The enzymes encoded by the GALNT [UDP-N-acetyl-α-d-galactosamine:polypeptide N-acetylgalactosaminyltransferase (GALNAC-T)] gene family catalyze the first step of O-glycosylation. Little is known about the link between expression of the genes encoding GALNAC-T enzymes and tumor progression in neuroblastoma, a pediatric cancer that can be classified as either low or high risk. We assessed the expression of genes in the GALNT family in a large cohort of neuroblastoma patients and characterized members of this family that might be used as new prognostic markers. METHODS Reverse-transcription PCR analysis of 14 GALNT genes with a panel of neuroblastoma cell lines identified the GALNT9 gene as playing a potential role in disease progression. We used the log-rank test and the multivariable Cox proportional hazards model with a cohort of 122 neuroblastoma patients to analyze the relationship between GALNT9 expression and overall survival or disease-free survival. RESULTS In the high-risk neuroblastoma experimental model IGR-N-91, GALNT9 expression was present in neuroblasts derived from primary tumors but not in neuroblasts from metastatic bone marrow. Moreover, GALNT9 in neuroblastoma cell lines was expressed in substrate adherent (S)-type cell lines but not in neuronal (N)-type lines. In the tumor cohort, GALNT9 expression was associated with high overall survival, independent of the standard risk-stratification covariates. GALNT9 expression was significantly associated with disease-free survival for patients currently classified as at low risk (P < 0.0007). CONCLUSIONS GALNT9 expression correlates with both improved overall survival in low- and high-risk groups and an improved clinical outcome (overall and disease-free survival) in low-risk patients. Thus, the GALNT9 expression may be a prognostic marker for personalized therapy.

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O-Glycan inhibitors generate aryl-glycans, induce apoptosis and lead to growth inhibition in colorectal cancer cell lines

Cited by 38 publications

References 48 publications

Glycomechanics of the Metastatic Cascade: Tumor Cell–Endothelial Cell Interactions in the Circulation

Glycomechanics of the Metastatic Cascade: Tumor Cell–Endothelial Cell Interactions in the Circulation

Glycosylation inhibition reduces cholesterol accumulation in NPC1 protein-deficient cells

GALNT9 Gene Expression Is a Prognostic Marker in Neuroblastoma Patients

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