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Tumor suppressor IRF-1 mediates retinoid and interferon anticancer signaling to death ligand TRAIL

Nicole Clarke1, Ana M Jimenez-Lara, Emilie Voltz

  • 1Department of Cell Biology and Signal Transduction, Institut de Génétique et de Biologie Moléculaire et Cellulaire/CNRS/INSERM/ULP, Illkirch, CU de Strasbourg, France.

The EMBO Journal
|July 9, 2004
PubMed

Insights

Retinoids and interferons boost anticancer TRAIL expression by activating IRF-1. This combination therapy shows synergistic tumor cell killing via TRAIL, sparing normal cells.

Area of Science:

  • Oncology
  • Molecular Biology
  • Immunology

Background:

  • Retinoids and interferons exhibit significant anticancer properties.
  • These signaling molecules are crucial in cellular communication and immune response.

Purpose of the Study:

  • To investigate the convergence of retinoid and interferon signaling pathways on the TRAIL promoter.
  • To elucidate the role of interferon regulatory factor-1 (IRF-1) in mediating the anticancer effects of retinoids and interferons.

Main Methods:

  • Promoter mapping, chromatin immunoprecipitation, and RNA interference were employed.
  • Coculture experiments were conducted to assess paracrine effects.

Main Results:

  • Retinoic acid (RA) and interferon-gamma (IFNγ) synergistically induce TRAIL expression through IRF-1.
  • IRF-1 is essential for RA- and IFNγ-mediated TRAIL induction.
  • Enhanced IRF-1 binding and histone acetylation at the TRAIL promoter were observed.
  • Pre-treated cancer cells induced TRAIL-dependent apoptosis in neighboring cancer cells (paracrine effect).

Conclusions:

  • IRF-1 possesses a novel TRAIL-mediated tumor suppressor activity.
  • A mechanistic basis for the synergistic anticancer effects of retinoids and interferons is identified.
  • Combination therapies targeting the TRAIL pathway offer a promising strategy for tumor eradication.

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