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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.
AuthorsI Brockhausen, J Yang, M Lehotay, S Ogata, S Itzkowitz
JournalBiological chemistry (Biol Chem) Vol. 382 Issue 2 Pg. 219-32 (Feb 2001) ISSN: 1431-6730 [Print] Germany
PMID11308020 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
Chemical References
  • Antigens, Tumor-Associated, Carbohydrate
  • Mucins
  • Polysaccharides
  • Tn antigen
  • N-Acetylglucosaminyltransferases
  • beta-1,3-galactosyl-O-glycosyl-glycoprotein beta-1,6-acetylglucosaminyl transferase
  • Sialyltransferases
  • beta-D-galactoside alpha 2-6-sialyltransferase
Topics
  • Amino Acid Sequence
  • Animals
  • Antigens, Tumor-Associated, Carbohydrate (genetics, metabolism)
  • Carbohydrate Sequence
  • Cell Division (genetics)
  • Colonic Neoplasms (metabolism, pathology)
  • Epithelial Cells (metabolism, pathology)
  • Gastric Mucosa (cytology, metabolism)
  • Glycosylation
  • Molecular Sequence Data
  • Mucins (chemistry, metabolism)
  • N-Acetylglucosaminyltransferases (metabolism)
  • Polysaccharides (chemistry, metabolism)
  • Rats
  • Reference Values
  • Sialyltransferases (metabolism)
  • Tumor Cells, Cultured

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