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TRAIL treatment provokes mutations in surviving cells

M M Lovric1, C J Hawkins

  • 1Department of Biochemistry, La Trobe Institute for Molecular Sciences, La Trobe University, Bundoora, Victoria, Australia.

Oncogene
|July 20, 2010
PubMed

Insights

Death ligand therapies like TRAIL can surprisingly cause mutations in surviving cancer cells, even though they don't primarily damage DNA. This unexpected DNA damage and mutagenesis highlights potential risks of these treatments.

Area of Science:

  • Cellular Biology
  • Molecular Oncology
  • Cancer Therapeutics

Background:

  • Chemotherapy and radiotherapy induce DNA damage and apoptosis, but can lead to treatment resistance and secondary malignancies.
  • Death ligand-based therapies (e.g., TRAIL) activate extrinsic apoptosis pathways, potentially bypassing resistance mechanisms.
  • It was hypothesized that extrinsic apoptosis pathways might spare surviving cells from genetic damage.

Purpose of the Study:

  • To investigate whether death ligand-based therapies, such as TRAIL, cause genetic damage in surviving cancer cells.
  • To determine the mechanisms underlying TRAIL-induced mutagenesis in non-malignant cells.

Main Methods:

  • Treatment of cells with sub-lethal concentrations of TRAIL or FasL.
  • Assessment of caspase activation and DNA damage.
  • Genetic manipulation including overexpression of caspase-8 inhibitors (crmA) and silencing of caspase-8.
  • Downregulation of caspase-activated DNAse (CAD)/DNA fragmentation factor 40 (DFF40).

Main Results:

  • Sub-lethal concentrations of TRAIL and FasL induced mutagenesis in surviving cells.
  • Mutagenesis was dependent on active caspases, specifically caspase-8.
  • Inhibition of caspase-8 or downregulation of CAD/DFF40 prevented TRAIL-induced DNA damage and mutagenesis.
  • Surviving cells sustained DNA damage despite death ligands not primarily targeting DNA.

Conclusions:

  • Death ligand-based therapies, contrary to initial hypotheses, can be mutagenic in surviving cells.
  • The extrinsic apoptosis pathway, while not directly damaging DNA, can trigger downstream events leading to genetic alterations.
  • Understanding these mechanisms is crucial for evaluating the safety and efficacy of death ligand therapies in cancer treatment.

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