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Tumour suppressor p16(INK4a) - anoikis-favouring decrease in N/O-glycan/cell surface sialylation by down-regulation of enzymes in sialic acid biosynthesis in tandem in a pancreatic carcinoma model.

Abstract
Tumour suppressor p16(INK4a) is known to exert cell-cycle control via cyclin-dependent kinases. An emerging aspect of its functionality is the orchestrated modulation of N/O-glycosylation and galectin expression to induce anoikis in human Capan-1 pancreatic carcinoma cells. Using chemoselective N/O-glycan enrichment technology (glycoblotting) and product characterization, we first verified a substantial decrease in sialylation. Tests combining genetic (i.e. transfection with α2,6-sialyltransferase-specific cDNA) or metabolic (i.e. medium supplementation with N-acetylmannosamine to track down a bottleneck in sialic acid biosynthesis) engineering with cytofluorometric analysis of lectin binding indicated a role of limited substrate availability, especially for α2,6-sialylation, which switches off reactivity for anoikis-triggering homodimeric galectin-1. Quantitative MS analysis of protein level changes confirmed an enhanced galectin-1 presence along with an influence on glycosyltransferases (β1,4-galactosyltransferase-IV, α2,3-sialyltransferase-I) and detected p16(INK4a) -dependent down-regulation of two enzymes in the biosynthesis pathway for sialic acid [i.e. the bifunctional UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) and N-acetylneuraminic acid 9-phosphate synthase] (P < 0.001). By contrast, quantitative assessment for the presence of nuclear CMP-N-acetylneuraminic acid synthase (which is responsible for providing the donor for enzymatic sialylation that also acts as feedback inhibitor of the epimerase activity of GNE) revealed a trend for an increase. Partial restoration of sialylation in GNE-transfected cells supports the implied role of sialic acid availability for the glycophenotype. Fittingly, the extent of anoikis was reduced in double-transfected (p16(INK4a) /GNE) cells. Thus, a second means of modulating cell reactivity to the growth effector galectin-1 is established in addition to the common route of altering α2,6-sialyltransferase expression: regulating enzymes of the pathway for sialic acid biosynthesis.
AuthorsMaho Amano, Hanna Eriksson, Joachim C Manning, Katharina M Detjen, Sabine André, Shin-Ichiro Nishimura, Janne Lehtiö, Hans-Joachim Gabius
JournalThe FEBS journal (FEBS J) Vol. 279 Issue 21 Pg. 4062-80 (Nov 2012) ISSN: 1742-4658 [Electronic] England
PMID22943525 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Copyright© 2012 The Authors Journal compilation © 2012 FEBS.
Chemical References
  • Cyclin-Dependent Kinase Inhibitor p16
  • Galectin 1
  • Lectins
  • Polysaccharides
  • Proteome
  • Phosphotransferases (Alcohol Group Acceptor)
  • N-acylmannosamine kinase
  • Carbohydrate Epimerases
  • UDP acetylglucosamine-2-epimerase
  • N-Acetylneuraminic Acid
Topics
  • Anoikis
  • Carbohydrate Epimerases (metabolism)
  • Cell Membrane (metabolism)
  • Cyclin-Dependent Kinase Inhibitor p16 (metabolism)
  • Galectin 1 (metabolism)
  • Gene Expression Regulation, Enzymologic
  • Genes, Tumor Suppressor
  • Glycosylation
  • Humans
  • Lectins (metabolism)
  • N-Acetylneuraminic Acid (metabolism)
  • Pancreatic Neoplasms (metabolism, pathology)
  • Phosphotransferases (Alcohol Group Acceptor) (metabolism)
  • Polysaccharides (metabolism)
  • Proteome
  • Spectrometry, Mass, Electrospray Ionization

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