Pathways of mucin O-glycosylation in normal and malignant rat colonic epithelial cells reveal a mechanism for cancer-associated Sialyl-Tn antigen expression.

Abstract:

:The Sialyl-Tn antigen (Sialyl alpha-Ser/Thr) is expressed as a cancer-associated antigen on the surface of cancer cells. Its presence is associated with a poor prognosis in patients with colorectal and other cancers. We previously reported that Sialyl-Tn expression in LSC human colon cancer cells could be explained by a specific lack of the activity of core 1 beta3-Gal-transferase (Brockhausen et al., Glycoconjugate J. 15, 595-603, 1998) and an inability to synthesize the common O-glycan core structures. To support this mechanism, or find other mechanisms to explain Sialyl-Tn antigen expression, we investigated the O-glycosylation pathways in clonal rat colon cancer cell lines that were selected for positive or negative expression of Sialyl-Tn antigen, and compared these pathways to those in normal rat colonic mucosa. Normal rat colonic mucosa had very active glycosyltransferases synthesizing O-glycan core structures 1 to 4. Several sialyl-, sulfo- and fucosyltransferases were also active. An M type core 2 beta6-GlcNAc-transferase was found to be present in rat colon mucosa and all of the rat colon cancer cells. O-glycosylation pathways in rat colon cancer cells were significantly different from normal rat colonic mucosa; for example, rat colon cancer cells lost the ability to synthesize O-glycan core 3. All rat colon cancer cell lines, regardless of the Sialyl-Tn phenotype, expressed glycosyltransferases assembling complex O-glycans of core 1 and core 2 structures (unlike human LSC colon cancer cells which lack core 1 beta3-Gal-transferase activity). It was the activity of CMP-sialic acid:GalNAc-mucin alpha6-sialyltransferase that coincided with Sialyl-Tn expression. Sialyl-Tn negative cells had a several fold higher activity of core 2 beta6-GlcNAc-transferase which synthesizes complex O-glycans that may mask adjacent Sialyl-Tn epitopes. The results suggest a new mechanism controlling Sialyl-Tn expression in cancer cells.

journal_name

Biol Chem

journal_title

Biological chemistry

authors

Brockhausen I,Yang J,Lehotay M,Ogata S,Itzkowitz S

doi

10.1515/BC.2001.029

keywords:

subject

Has Abstract

pub_date

2001-02-01 00:00:00

pages

219-32

issue

2

eissn

1431-6730

issn

1437-4315

journal_volume

382

pub_type

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