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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., Author(s): Klaus W Wagner [1, 7, 8]; Elizabeth A Punnoose [1, 2, 8]; Thomas Januario [1]; David A Lawrence [2]; Robert M Pitti [2]; Kate Lancaster [3]; Dori Lee [1]; [...]

Activated T cells and natural killer cells produce fast ligand (FasL), which induces apoptosis. FasL and Fas mediate immune-cytotoxic killing of potentially harmful cells. A soluble decoy receptor, termed decoy receptor 3 (DcR3) has been discovered, that binds to FasL and restricts FasL-induced apoptosis. This gene was amplified in around half of the 35 primary lung and colon tumours examined.