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

Klaus W Wagner1, Elizabeth A Punnoose, Thomas Januario

  • 1Department of Molecular Diagnostics, Genentech, Inc., 1 DNA Way, South San Francisco, California 94080, USA.

Nature Medicine
|September 4, 2007
PubMed

Insights

The peptidyl O-glycosyltransferase GALNT14 gene regulates sensitivity to Apo2L/TRAIL cancer therapy. GALNT14 O-glycosylation of death receptors DR4/DR5 enhances cancer cell death signaling, offering potential predictive biomarkers.

Area of Science:

  • Molecular biology
  • Cancer research
  • Glycobiology

Background:

  • Apo2L/TRAIL (TNF-related apoptosis-inducing ligand) induces cancer cell death via DR4 and DR5 receptors.
  • Tumor susceptibility to Apo2L/TRAIL therapy is not fully understood.

Purpose of the Study:

  • To investigate the role of GALNT14 in Apo2L/TRAIL sensitivity.
  • To elucidate the mechanism of O-glycosylation in death receptor function.

Main Methods:

  • Correlating GALNT14 mRNA expression with Apo2L/TRAIL sensitivity in cancer cell lines.
  • Utilizing RNA interference and overexpression to study GALNT14 function.
  • Biochemical analysis and site-directed mutagenesis of DR5 O-glycosylation sites.

Main Results:

  • GALNT14 expression positively correlated with Apo2L/TRAIL sensitivity across multiple cancer types.
  • GALNT14 knockdown decreased sensitivity; overexpression increased responsiveness.
  • O-glycosylation of DR4/DR5 ectodomains, mediated by GALNT14, promoted receptor clustering and caspase-8 activation, enhancing apoptosis.

Conclusions:

  • GALNT14-mediated O-glycosylation of DR4/DR5 is a key determinant of cancer cell response to Apo2L/TRAIL.
  • GALNT14 and DR4/DR5 O-glycosylation patterns may serve as predictive biomarkers for Apo2L/TRAIL cancer therapy.

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