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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-3 inhibitors augment TRAIL-induced apoptotic death in human hepatoma cells

Eléonore Beurel1, Marie-José Blivet-Van Eggelpoël, Michel Kornprobst

  • 1UPMC Univ Paris 06, UMR_S 893, F-75005, INSERM, UMR_S 893, Centre de Recherche Saint-Antoine, F-75012, Paris, France.

Biochemical Pharmacology
|October 22, 2008
PubMed

Insights

Glycogen synthase kinase-3 (GSK-3) inhibitors restore sensitivity to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) in hepatocellular carcinoma (HCC) cells. These inhibitors enhance apoptosis, offering new therapeutic strategies for HCC treatment.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Hepatocellular carcinoma (HCC) exhibits significant resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.
  • Identifying agents to overcome TRAIL resistance is crucial for developing novel HCC therapies.

Purpose of the Study:

  • To investigate whether glycogen synthase kinase-3 (GSK-3) inhibitors can re-sensitize hepatoma cells to TRAIL-induced apoptosis.
  • To elucidate the molecular mechanisms underlying the sensitization effect.

Main Methods:

  • Human hepatoma cell lines and normal hepatocytes were treated with GSK-3 inhibitors (lithium, SB-415286) and TRAIL.
  • Caspase-8 activity, p53 levels, and c-Jun N-terminal kinase (JNK) activation were assessed.
  • RNA interference was used to down-regulate p53.
  • JNK inhibitors (AS601245, SP600125) were employed to study JNK's role.

Main Results:

  • GSK-3 inhibitors sensitized hepatoma cells, but not normal hepatocytes, to TRAIL-induced apoptosis by increasing caspase-8 activity.
  • GSK-3 inhibition stabilized p53, and p53 down-regulation abolished lithium's sensitizing effect on caspase-3 activation.
  • GSK-3 inhibitors activated JNKs; however, JNK inhibition led to enhanced apoptosis, suggesting a protective role for JNK signaling.
  • GSK-3 negatively regulates TRAIL-induced apoptosis in hepatoma cells.

Conclusions:

  • GSK-3 inhibitors can overcome TRAIL resistance in HCC by enhancing apoptosis through caspase-8 and p53 pathways.
  • Activated JNK signaling appears to provide an anti-apoptotic balance, counteracting the pro-apoptotic effects of GSK-3 inhibitors.
  • GSK-3 inhibitors represent a promising therapeutic strategy to augment TRAIL-based anti-cancer activity in HCC.

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