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Pathways of O-glycan biosynthesis in cancer cells

Some of the mechanisms of changes in O -glycosylation pathways have been determined in cancer model systems.

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Pathways of O -glycan biosynthesis in cancer cells - DeepDyve

NK cells are activated through the NK cell-targetcell interaction and release their granular contents to kill thetarget cells. The granular contents include perforin and granzyme Bwhich induce apoptosis of the target cells. We measured thesecretion of granzyme B stimulated by the NK cell-prostate cancercell interaction using an assay of the protease activity ofgranzyme B in the co-culture supernatant. The C2GnT-expressing PC3cells induced the secretion of significantly lower levels ofgranzyme B than the C2GnT-deficient C2KD-1 cells (). These results suggest that MUC1glycoproteins carrying poly--acetyllactosamine attenuatethe NK cell-prostate cancer cell interaction, resulting indecreased secretion of granzyme B ().

Map 2: Biosynthetic Pathways of O-Glycans | SpringerLink

One of the major prognostic determinants of cancerpatients is metastasis. The process of metastasis involves multiplesteps (). A growing body ofevidence supports crucial roles for cell-surface carbohydratesduring the process of metastasis. Cell-surface carbohydratespresented by glycoproteins are classified in accordance with theirlinkage to proteins and comprise -glycans[-acetylglucosamine (GlcNAc) to asparagine] and-glycans [-acetylgalactosamine (GalNAc) to serine(Ser) or threonine (Thr)]. It has been reported that-glycans are involved in several steps of the metastaticprocess (), but the roles of-glycans remain unclear. We have concentrated our effortson understanding the roles of -glycans in tumormetastasis.

Map 2: Biosynthetic Pathways of O-Glycans

reflecting cancer-specific changes in glycan biosynthesis pathways such as ..

The core2 branch is a scaffold for the subsequentproduction of lactosamine disaccharide repeats, specificallypoly--acetyllactosamine (Galβ1-4GlcNAc)n () (). To determine whether MUC1 from PC3cells carries poly--acetyllactosamine on its-glycans, we first excluded -glycans from prostatecancer cells by treatment with tunicamycin, an-glycosylation inhibitor, and then analyzed the celllysates by immunoprecipitation using LEL. LEL binds specifically topoly--acetyllactosamines with at least three lactosamineunit repeats. The LEL immunoprecipitates were subjected to westernblotting with anti-MUC1 antibody. MUC1 was detected in the LELimmunoprecipitates from the PC3 cells, but the amount of MUC1detected in the LEL immunoprecipitates from the C2KD-1 cells wasmarkedly reduced (, lanes 7and 8). This result indicates that MUC1 from C2GnT-expressing PC3cells carries a larger amount of poly--acetyllactosamine onits core2 -glycans than that from C2KD-1 cells.

NK cells play a critical role in tumor rejectionresponses in the host blood circulation. The attack on cancer cellsby NK cells is initiated by the NK cell-cancer cell interactionmediated through the NK receptor-ligand interaction (). To determine whether C2GnTexpression affects the NK cell-prostate cancer cell interaction, wecompared the conjugate formation of NK cells with PC3 and C2KD-1cells. Following the incubation of the target cells with NK cellsfor 1 h, the NK cells formed a significantly higher number ofconjugates with the C2KD-1 cells than with the PC3 cells (). This result, taken together with, suggests that in theC2GnT-expressing cells (PC3), the poly--acetyllactosaminemoieties carried by the MUC1 core2 -glycans reduce theadhesive properties of MUC1 due to their bulkiness, resulting inreduced conjugate formation between the PC3 and NK cells ().

Some of the enzymes with roles in glycan biosynthesis include ..

The disadvantage of these types of inhibitor is that they affect all N-glycan biosynthesis, ..

We have previously shown that MUC1 is modified bypoly--acetyllactosamine on its -glycan residues inC2GnT-expressing prostate cancer cells. MUC1 is significant inadhesion as it is one of the molecules that extends most highlyabove the cell surface (). Ourresults taken together with this observation suggest that themodification of MUC1 in C2GnT-expressing prostate cancer cells withbulky poly--acetyllactosamine moieties reduces theiradhesiveness, thereby attenuating the NK cell-cancer cellinteraction. The attenuated interaction results in decreaseddegranulation by NK cells and reduction of the accessibility ofTRAIL to the death receptors (). These effects allow C2GnT-expressing prostate cancer cellsto evade NK cell immunity in the circulation. In our previousstudy, when bladder tumor cells were intravenously injected intonude mice, C2GnT-expressing tumor cells produced a greater numberof metastatic foci in the lungs than were produced byC2GnT-non-expressing tumor cells (). Our present data taken together withthe previous observations strongly suggest that this immune evasionresults in longer survival of C2GnT-expressing prostate cancercells in the host blood circulation, resulting in the promotion ofprostate cancer metastasis.

Wagner reported that tumor-cellsensitivity to TRAIL was controlled by -glycosylation ofdeath receptors (DR4 and DR5). In 22 out of 28 TRAIL-sensitivecancer cell lines, the expression levels of a peptidyl-glycosyltransferase which catalyzes the initial step of-glycosylation were elevated (). It was shown that-glycosylation of death receptors promoted TRAIL-stimulatedclustering of the receptors, mediating recruitment and activationof the apoptosis-initiating protease, caspase-8. Although their-glycan structures were not analyzed,-glycosylation increased the TRAIL-sensitivity of thecancer cells. The authors observed -glycosylation of deathreceptors on the western blots of 22 of the 28 TRAIL-sensitive celllines. However, no significant -glycosylation of DR4 wasobserved in the present study, suggesting that C2GnT-expressingprostate cancer cells use a different mechanism to control cancercell-sensitivity to TRAIL from that reported by Wagner .

Glycoproteins with O-glycosidically linked carbohydrate chains of complex structures and functions are found in secretions and on the cell surfaces of cancer cells.
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  • Colon cancer cells simplify O‐glycan ..

    12/6/1999 · 1


    Biochim Biophys Acta

  • KEGG PATHWAY: map00512 - Genome

    1999 Dec 6;1473(1):67-95

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Depending on the sugars added, there are four common O-glycan core ..

Simon GM, Cravatt BF. (2010)Characterization of mice lacking candidate N-acyl ethanolamine biosynthetic enzymes provides evidence formultiple pathways that contribute to endocannabinoid production in vivo.
Mol Biosyst. 6(8):1411-8.

O-glycan biosynthesis, mucin type ..

Metabolism1.0 Global and overview maps1.1 Carbohydrate metabolism1.2 Energy metabolism1.3 Lipid metabolism1.4 Nucleotide metabolism1.5 Amino acid metabolism1.6 Metabolism of other amino acids1.7 Glycan biosynthesis and metabolism1.8 Metabolism of cofactors and vitamins1.9 Metabolism of terpenoids and polyketides1.10 Biosynthesis of other secondary metabolites1.11 Xenobiotics biodegradation and metabolism1.12 Chemical structure transformation maps

Aberrant Glycosylation as Biomarker for Cancer ..

Manna JD, Wepy JA, Hsu K, Chang JW, Cravatt BF, Marnett LJ. (2014) Identification of the Major Prostaglandin Glycerol Ester Hydrolase in Human Cancer Cells. J Biol Chem 2014 Oct 9. [Epub ahead of print]

for BioMed Research International, ..

NK cells use two main mechanisms to kill tumorcells. One is that NK cells are activated through the NK cellreceptor-tumor ligand interaction to release cytotoxic granules,including perforin and granzymes. The other is that NK cells killtumor cells using death ligands, including TRAIL (). TRAIL induces target cell apoptosisthrough its interaction with death receptors, including DR4, on thesurface of the target cell. We evaluated the expression of DR4 onthe prostate cancer cells by western blotting. We observed nosignificant differences in the DR4 expression levels between PC3and C2KD-1 (, lanes 1 and2). Unlike MUC1, no significant differences in the-glycosylation levels of DR4 between PC3 and C2KD-1 cellswere observed on western blots ( and ). To evaluate theeffect of C2GnT expression on the sensitivity of prostate cancercells to TRAIL, we measured TRAIL-induced cell death using solublerecombinant TRAIL. In the presence of TRAIL, the viability of thePC3 cells was significantly higher than that of the C2KD-1 cells(), indicating thatC2GnT-expressing prostate cancer cells are more resistant to TRAILthan are C2GnT-deficient cells.

cancer metastasis and anti-cancer vaccines

Studies of their regulation in cancer may reveal the connection between cancerous transformation and glycosylation which may help to understand and control the abnormal biology of tumor cells.

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