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Regulation of pancreatic cancer TRAIL resistance by protein O-GlcNAcylation

Shan-Zhong Yang1, Fei Xu1,2, Kaiyu Yuan1

  • 1Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA.

Laboratory Investigation; a Journal of Technical Methods and Pathology
|January 4, 2020
PubMed

Insights

Protein O-GlcNAcylation enhances pancreatic cancer cell resistance to TRAIL-activating therapy by modifying DR5. Inhibiting O-GlcNAcylation with OGT knockdown restores TRAIL sensitivity and promotes apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • TRAIL-activating therapy shows promise for pancreatic cancer but faces resistance.
  • Protein O-GlcNAcylation, a posttranslational modification, is implicated in cancer cell growth and survival.
  • Pancreatic cancer cells often exhibit resistance to TRAIL-induced apoptosis despite expressing death receptors.

Purpose of the Study:

  • To investigate the role of protein O-GlcNAcylation in pancreatic cancer TRAIL resistance.
  • To determine if O-GlcNAcylation levels correlate with TRAIL resistance in pancreatic cancer.
  • To elucidate the molecular mechanisms by which O-GlcNAcylation influences TRAIL signaling.

Main Methods:

  • Assessed O-GlcNAcylation levels in TRAIL-resistant pancreatic cancer cells.
  • Utilized gain- and loss-of-function approaches for O-GlcNAc-transferase (OGT).
  • Evaluated TRAIL-induced apoptosis in vitro and in vivo (mouse model) following OGT manipulation.
  • Performed mechanistic studies to identify direct O-GlcNAc modifications on death receptor 5 (DR5).

Main Results:

  • TRAIL-resistant pancreatic cancer cells displayed higher O-GlcNAcylation levels.
  • Increased O-GlcNAcylation conferred TRAIL resistance, while OGT inhibition sensitized cells to TRAIL-8-induced apoptosis.
  • OGT knockdown in vivo sensitized TRAIL-resistant tumors to TRAIL-8 therapy.
  • Direct O-GlcNAc modification of DR5 was identified, regulating TRAIL-8-induced DR5 oligomerization independently of FADD.

Conclusions:

  • Protein O-GlcNAcylation plays a critical role in mediating TRAIL resistance in pancreatic cancer.
  • O-GlcNAcylation directly impacts DR5 oligomerization, thereby influencing TRAIL-induced signaling pathways.
  • Targeting O-GlcNAcylation represents a potential therapeutic strategy to overcome TRAIL resistance in pancreatic cancer.

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