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Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

Glycogen synthase kinase-3beta suppression eliminates tumor necrosis factor-related apoptosis-inducing ligand

Xinbo Liao1, Liping Zhang, J Brantley Thrasher

  • 1Department of Urology and Kansas Cancer Institute, The University of Kansas Medical Center, Kansas City, KS, USA.

Molecular Cancer Therapeutics
|November 18, 2003
PubMed

Insights

Suppression of glycogen synthase kinase-3beta (GSK-3beta) enhances tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in prostate cancer cells. This sensitization is mediated by caspase-8 activation, offering new therapeutic strategies for prostate cancer treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Biochemistry

Background:

  • Prostate cancer represents a significant health concern for men, necessitating the development of effective therapeutic strategies.
  • Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) has shown potential in inducing apoptosis in cancer cells, but resistance mechanisms exist.
  • Glycogen synthase kinase-3beta (GSK-3beta) is implicated in various cellular processes, including apoptosis regulation.

Purpose of the Study:

  • To investigate the effect of suppressing glycogen synthase kinase-3beta (GSK-3beta) on TRAIL-induced apoptosis in human prostate cancer cell lines.
  • To elucidate the molecular mechanisms underlying GSK-3beta's role in TRAIL-mediated cell death and potential resistance.

Main Methods:

  • Human prostate cancer cell lines were treated with GSK-3beta inhibitors (lithium chloride, SB216763) or subjected to GSK-3beta gene silencing via siRNA.
  • Cells were subsequently exposed to TRAIL, and apoptosis was assessed using Annexin V labeling and caspase-3 activation assays.
  • Caspase-8 activation, BID cleavage, and nuclear factor-kappaB (NF-kappaB) activity were analyzed to determine signaling pathways involved.

Main Results:

  • Inhibition or silencing of GSK-3beta significantly enhanced TRAIL-induced apoptosis, evidenced by increased Annexin V staining and caspase-3 activation.
  • TRAIL stimulation led to increased GSK-3beta phosphorylation at Y216, indicating GSK-3beta activation by TRAIL.
  • Enhanced TRAIL sensitivity was associated with increased caspase-8 activation and BID cleavage, which was reversed by a caspase-8 inhibitor.
  • GSK-3beta inhibition enhanced TRAIL-induced apoptosis independently of NF-kappaB pathway modulation.

Conclusions:

  • Suppression of GSK-3beta sensitizes prostate cancer cells to TRAIL-induced apoptosis through a mechanism dependent on caspase-8 activation.
  • GSK-3beta activation by TRAIL may contribute to TRAIL resistance in prostate cancer.
  • Targeting GSK-3beta in combination with TRAIL presents a potential therapeutic strategy for overcoming TRAIL resistance in prostate cancer.

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