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Updated: Jan 31, 2026

Identification of Mediators of T-cell Receptor Signaling via the Screening of Chemical Inhibitor Libraries
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GSK-3 inhibitors enhance TRAIL-mediated apoptosis in human gastric adenocarcinoma cells

Yi-Ying Wu1,2,3, Chin-Tung Hsieh4, Ying-Ming Chiu5,6

  • 1Department of Medical Laboratory Science and Biotechnology, China Medical University, Taichung, Taiwan.

Plos One
|December 18, 2018
PubMed

Insights

Glycogen synthase kinase-3 (GSK-3) inhibitors can resensitize gastric cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis. This suggests GSK-3 inhibitors may enhance TRAIL

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Resistance to TRAIL-induced apoptosis is observed in gastric adenocarcinoma.
  • Targeting this resistance is crucial for effective gastric cancer treatment.

Purpose of the Study:

  • To investigate if GSK-3 inhibitors can restore TRAIL sensitivity in gastric adenocarcinoma cells.
  • To elucidate the molecular mechanisms underlying GSK-3 inhibitor-mediated sensitization to TRAIL.

Main Methods:

  • Treatment of gastric adenocarcinoma cell lines and primary cells with GSK-3 inhibitors (SB-415286, LiCl) and TRAIL.
  • Analysis of apoptosis signaling pathways, including caspase-8, caspase-3, p53, and JNK.
  • Utilized siRNA to downregulate p53 expression.

Main Results:

  • GSK-3 inhibitors sensitized gastric adenocarcinoma cells, but not normal gastric cells, to TRAIL-induced apoptosis.
  • Sensitization was associated with increased caspase-8 activity and downstream signaling.
  • p53 siRNA partially reversed the sensitization effect.
  • GSK-3 inhibitors strongly activated JNK phosphorylation, which appeared to have an anti-apoptotic role.

Conclusions:

  • GSK-3 inhibitors can overcome TRAIL resistance in AGS gastric adenocarcinoma cells.
  • GSK-3 inhibitors enhance TRAIL's antitumor activity by modulating apoptosis pathways.
  • GSK-3 inhibitors represent a potential therapeutic strategy for specific gastric adenocarcinomas.

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