Tumour suppressor p16INK4a – 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

Tumour suppressor p16INK4a 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‐gl...

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Bibliographic Details
Published in:The FEBS journal 2012-11, Vol.279 (21), p.4062-4080
Main Authors: Amano, Maho, Eriksson, Hanna, Manning, Joachim C., Detjen, Katharina M., André, Sabine, Nishimura, Shin‐Ichiro, Lehtiö, Janne, Gabius, Hans‐Joachim
Format: Article
Language:English
Subjects:
anoikis
Biosynthesis
glycosyltransferase
integrin
Kinases
lectin
Pancreatic cancer
proteomics
Tumors
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Summary:Tumour suppressor p16INK4a 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 p16INK4a‐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 
ISSN:1742-464X
1742-4658
DOI:10.1111/febs.12001