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Bid mediates apoptotic synergy between tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and DNA damage

V Courtney Broaddus1, Tobias B Dansen, Keith S Abayasiriwardana

  • 1Lung Biology Center, San Francisco General Hospital, University of California San Francisco, San Francisco, California 94143-0854, USA. sfcourt@itsa.ucsf.edu

The Journal of Biological Chemistry
|December 24, 2004
PubMed

Insights

Combining TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) with DNA-damaging agents like etoposide enhances cancer cell death. DNA damage sensitizes cells to activated Bid, a protein crucial for this synergistic apoptosis, revealing a new therapeutic strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • TRAIL (tumor necrosis factor-related apoptosis-inducing ligand) induces apoptosis selectively in tumors.
  • Many tumor cells exhibit resistance to TRAIL-induced apoptosis alone.
  • Co-treatment with DNA-damaging agents can sensitize resistant tumor cells to TRAIL.

Purpose of the Study:

  • To elucidate the molecular mechanism behind the synergistic apoptosis induced by TRAIL and DNA-damaging agents in human mesothelioma cells.
  • To investigate the role of Bid protein activation in TRAIL-etoposide mediated apoptotic synergy.
  • To determine the causal relationship between caspase 8 cleavage and the apoptotic cascade in this synergistic effect.

Main Methods:

  • Utilized human mesothelioma cell lines, known for therapeutic resistance.
  • Investigated the role of Bid protein activation in response to TRAIL ligation and DNA damage.
  • Analyzed caspase 8 cleavage patterns during combined TRAIL and etoposide treatment.

Main Results:

  • Bid protein is essential for the synergistic apoptotic effect of TRAIL and etoposide.
  • DNA damage primes cells to undergo apoptosis induced by sublethal levels of activated Bid.
  • Extensive caspase 8 cleavage is a downstream consequence, not the cause, of the Bid-activated apoptotic cascade.

Conclusions:

  • TRAIL-etoposide apoptotic synergy occurs because DNA damage enhances cellular sensitivity to TRAIL-activated Bid.
  • This mechanism highlights how combining proapoptotic signals can overcome tumor refractoriness.
  • The findings suggest a potential therapeutic strategy for treating resistant cancers through combined signaling pathways.

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