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DR5-mediated DISC controls caspase-8 cleavage and initiation of apoptosis in human glioblastomas

Anita C Bellail1, Margaret C L Tse, Jin H Song

  • 1Department of Pathology and Laboratory Medicine, Winship Cancer Institute, Emory University School Medicine, Atlanta, GA 30322, USA.

Journal of Cellular and Molecular Medicine
|May 13, 2009
PubMed

Insights

Glioblastomas resist TRAIL-induced apoptosis due to modified death-inducing signaling complexes (DISCs) involving RIP, c-FLIP, and PED/PEA-15. Inhibiting these factors restores DISC function and TRAIL sensitivity in glioblastoma cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Glioblastomas often exhibit resistance to apoptosis-inducing agents like tumor necrosis factor-related apoptosis-inducing ligand (TRAIL).
  • Understanding the molecular mechanisms of TRAIL resistance is crucial for developing effective glioblastoma therapies.

Purpose of the Study:

  • To elucidate the molecular pathways conferring TRAIL resistance in glioblastomas.
  • To identify key molecular players involved in the dysregulation of TRAIL signaling in resistant glioblastoma cells.

Main Methods:

  • Analysis of TRAIL receptor expression (DR4/5, DcR1/2) in glioblastoma cell lines and tissues.
  • Investigation of death-inducing signaling complex (DISC) assembly and composition in TRAIL-sensitive versus resistant cells.
  • Utilized small interfering RNA (siRNA) to target specific proteins (RIP, c-FLIP, PED/PEA-15) and assessed the impact on TRAIL sensitivity.

Main Results:

  • Death receptor 5 (DR5) is consistently expressed in glioblastomas, while decoy receptors are not implicated in resistance.
  • In resistant cells, the DISC is modified by receptor-interacting protein (RIP), cellular FADD-like interleukin-1beta-converting enzyme inhibitory protein (c-FLIP), and phosphoprotein enriched in diabetes or in astrocyte-15 (PED/PEA-15) in non-raft membrane fractions.
  • This modification inhibits caspase-8 activation and promotes nuclear factor-kappaB (NF-kappaB) activity, leading to TRAIL resistance.
  • Targeting RIP, c-FLIP, or PED/PEA-15 with siRNA restored DISC function in lipid rafts, enabling caspase-8 cleavage and overcoming TRAIL resistance.

Conclusions:

  • DISC modification by RIP, c-FLIP, and PED/PEA-15 is the primary upstream event driving TRAIL resistance in glioblastomas.
  • These proteins disrupt DISC assembly in lipid rafts, preventing caspase-8 activation and subsequent apoptosis.
  • Targeting these specific proteins represents a potential therapeutic strategy to re-sensitize glioblastomas to TRAIL-based therapies.

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