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Playing the DISC: turning on TRAIL death receptor-mediated apoptosis in cancer

Bodvaël Pennarun1, Annemieke Meijer, Elisabeth G E de Vries

  • 1Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.

Biochimica Et Biophysica Acta
|December 8, 2009
PubMed

Insights

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) triggers cancer cell death by forming the death-inducing signaling complex (DISC). Understanding DISC assembly and caspase activation is key to developing effective TRAIL-based cancer therapies.

Area of Science:

  • Molecular Biology
  • Cell Biology
  • Cancer Research

Background:

  • The death-inducing signaling complex (DISC) formation is initiated by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) binding to its receptors TRAIL-R1 and TRAIL-R2 on cancer cells.
  • Key DISC components include trimerized TRAIL-R1/-R2, FADD, caspase 8, and caspase 10, with FLIP potentially inhibiting apoptosis.
  • Caspase 8/10 activation at the DISC initiates a cascade leading to programmed cell death.

Purpose of the Study:

  • To review factors influencing TRAIL-mediated apoptosis signaling pathway initiation.
  • To focus on mechanisms modulating DISC assembly and caspase activation.
  • To guide the rational design of combination therapies involving TRAIL receptor ligands.

Main Methods:

  • Literature review of TRAIL-mediated apoptosis.
  • Analysis of DISC formation and caspase activation mechanisms.
  • Discussion of preclinical combination therapy models.

Main Results:

  • TRAIL receptor ligands, including selective variants and agonistic antibodies, are investigated as anti-cancer agents.
  • TRAIL receptor ligands show potential in selectively killing tumor cells.
  • Combination therapies are explored to enhance tumor sensitivity and overcome drug resistance.

Conclusions:

  • Insights into DISC assembly and caspase activation are crucial for optimizing TRAIL-based cancer treatments.
  • Understanding these mechanisms can lead to improved drug combinations for enhanced anti-cancer efficacy.
  • Targeting DISC signaling offers a promising strategy for developing novel cancer therapies.

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