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Intracellular mechanisms of TRAIL: apoptosis through mitochondrial-dependent and -independent pathways

A Suliman1, A Lam, R Datta

  • 1Department of Pharmaceutical Sciences, University of Maryland - School of Pharmacy, 20 N Pine Street, Baltimore, Maryland MD 21201, USA.

Oncogene
|May 22, 2001
PubMed

Insights

Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) triggers programmed cell death in cancer cells. This study reveals TRAIL utilizes death receptors (DR4/DR5) and adaptor protein FADD to initiate apoptosis through caspase activation and mitochondrial pathways.

Area of Science:

  • Cell Biology
  • Molecular Biology
  • Immunology

Background:

  • Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a cytokine that induces apoptosis in tumor cells.
  • TRAIL signals through death receptors (DR4 and DR5), but its intracellular mechanisms are not fully understood.
  • The role of adaptor protein FADD in TRAIL-induced apoptosis is unclear.

Purpose of the Study:

  • To investigate the intracellular signaling pathways of TRAIL-induced apoptosis.
  • To determine the involvement of FADD and caspases in TRAIL signaling.
  • To elucidate the contribution of mitochondrial pathways to TRAIL-mediated cell death.

Main Methods:

  • Analysis of signaling complex assembly upon TRAIL binding to DR4/DR5.
  • Assessment of apoptosis in cells deficient in FADD or caspase-8.
  • Evaluation of mitochondrial events (e.g., loss of potential, cytochrome c release) and caspase activation.
  • Inhibition studies using cyclosporin A, Bcl-2, Bcl-X(L), XIAP, CrmA, and p35.

Main Results:

  • TRAIL induces the assembly of a signaling complex involving DR4/DR5, FADD, and caspase-8.
  • FADD and caspase-8 are essential for TRAIL-induced apoptosis; caspase-10 is not involved.
  • TRAIL triggers caspase activation, mitochondrial potential loss, BID cleavage, and cytochrome c release.
  • Inhibitors of apoptosis (XIAP, CrmA, p35) block TRAIL-induced cell death, while cyclosporin A and Bcl-2/Bcl-X(L) only delay it.

Conclusions:

  • TRAIL-induced apoptosis utilizes a pathway similar to Fas receptor signaling, involving FADD and caspase-8.
  • TRAIL-mediated apoptosis involves both mitochondrial-dependent and -independent pathways.
  • Understanding these mechanisms can inform cancer therapy strategies targeting TRAIL signaling.

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