Death-receptor O-glycosylation controls tumor-cell sensitivity to the proapoptotic ligand Apo2L/TRAIL

Nat Med. 2007 Sep;13(9):1070-7. doi: 10.1038/nm1627. Epub 2007 Sep 2.


Apo2L/TRAIL stimulates cancer cell death through the proapoptotic receptors DR4 and DR5, but the determinants of tumor susceptibility to this ligand are not fully defined. mRNA expression of the peptidyl O-glycosyltransferase GALNT14 correlated with Apo2L/TRAIL sensitivity in pancreatic carcinoma, non-small-cell lung carcinoma and melanoma cell lines, and up to 30% of samples from various human malignancies showed GALNT14 overexpression. RNA interference of GALNT14 reduced cellular Apo2L/TRAIL sensitivity, whereas overexpression increased responsiveness. Biochemical analysis of DR5 identified several ectodomain O-(N-acetyl galactosamine-galactose-sialic acid) structures. Sequence comparison predicted conserved extracellular DR4 and DR5 O-glycosylation sites; progressive mutation of the DR5 sites attenuated apoptotic signaling. O-glycosylation promoted ligand-stimulated clustering of DR4 and DR5, which mediated recruitment and activation of the apoptosis-initiating protease caspase-8. These results uncover a new link between death-receptor O-glycosylation and apoptotic signaling, providing potential predictive biomarkers for Apo2L/TRAIL-based cancer therapy.

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Apoptosis
  • Carcinoma, Non-Small-Cell Lung
  • Cell Line, Tumor
  • Cell Survival
  • Genetic Predisposition to Disease
  • Glycosylation
  • Humans
  • Lung Neoplasms
  • Melanoma
  • Mice
  • Molecular Sequence Data
  • Oligonucleotide Array Sequence Analysis
  • Pancreatic Neoplasms
  • RNA, Messenger / genetics
  • Receptors, Death Domain / physiology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / genetics
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / physiology*
  • Transplantation, Heterologous


  • RNA, Messenger
  • Receptors, Death Domain
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFSF10 protein, human

Associated data

  • GEO/GSE8332