Down-regulation of β-N-acetyl-D-glucosaminidase increases Akt1 activity in thyroid anaplastic cancer cells.

Abstract

O-GlcNAcylation is a common and dynamic modification of intracellular proteins in which β-N-acetyl-glucosamine moieties are attached to hydroxyl groups of serine or threonine residues (O-GlcNAc). Accumulating evidence suggests the critical role of protein O-GlcNAcylation in signal transduction, transcriptional control, cell cycle regulation and protein degradation. However, the exact role of O-GlcNAc modification in tumor pathogenesis or progression remains to be established. In the present study, we investigated the effect of increased O-GlcNAcylation of cellular proteins on IGF‑1 signaling in 8305C thyroid anaplastic cancer cells. The global O-GlcNAc level in the 8305C cells was increased by down-regulation of β-N-acetyl-D-glucosaminidase (O-GlcNAcase) activity, an enzyme which removes O-GlcNAc moieties. We demonstrated here that IGF‑1 stimulates Akt1 activity in 8305C cells, and down-regulation of O-GlcNAcase activity by the chemical inhibitor PUGNAc or RNA interference method enhances this effect. Increased Akt1 activation increased cell proliferation. In cells with down-regulation of O-GlcNAcase activity, kinase GSK3β phosphorylation and cyclin D1 levels were higher than those in control cells. Our findings suggest that increased proliferation of 8305C cells treated with PUGNAc or RNAi against O-GlcNAcase at least partially depends on the IGF‑1-Akt1-GSK3β-cyclin D1 pathway.

• Authors: Anna Krześlak, Paweł Jóźwiak, Anna Lipińska
• Journal: Oncology reports (Oncol Rep) Vol. 26 Issue 3 Pg. 743-9 (Sep 2011) ISSN: 1791-2431 [Electronic] Greece
• PMID: 21637923 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• CCND1 protein, human
• Oximes
• Phenylcarbamates
• N-acetylglucosaminono-1,5-lactone O-(phenylcarbamoyl)oxime
• Cyclin D1
• Insulin-Like Growth Factor I
• AKT1 protein, human
• GSK3B protein, human
• Glycogen Synthase Kinase 3 beta
• Proto-Oncogene Proteins c-akt
• Glycogen Synthase Kinase 3
• beta-N-Acetylhexosaminidases
• Acetylglucosamine

Topics

• Acetylglucosamine (analogs & derivatives, pharmacology)
• Cell Line, Tumor
• Cell Proliferation
• Cell Survival
• Cyclin D1 (metabolism)
• Down-Regulation
• Glycogen Synthase Kinase 3 (metabolism)
• Glycogen Synthase Kinase 3 beta
• Humans
• Insulin-Like Growth Factor I (pharmacology, physiology)
• Oximes (pharmacology)
• Phenylcarbamates (pharmacology)
• Phosphorylation
• Proto-Oncogene Proteins c-akt (metabolism)
• RNA Interference
• Thyroid Neoplasms (metabolism)
• beta-N-Acetylhexosaminidases (antagonists & inhibitors, genetics, metabolism)