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Regulation of interferon and retinoic acid-induced cell death activation through thioredoxin reductase

X Ma1, S Karra, W Guo

  • 1Greenebaum Cancer Center, Department of Microbiology and Immunology, Molecular and Cellular Biology Program, University of Maryland School of Medicine, Baltimore, MD 21201, USA.

The Journal of Biological Chemistry
|May 2, 2001
PubMed

Insights

The combination of Interferon-beta (IFN) and all-trans-retinoic acid induces tumor cell death by activating thioredoxin reductase (TR). TR modulates caspase activity and death receptor expression, revealing a novel cell death mechanism involving redox enzymes.

Area of Science:

  • Molecular biology
  • Cellular signaling
  • Cancer research

Background:

  • Interferons (IFNs) and retinoids are biological response modifiers.
  • The combination of IFN-beta and all-trans-retinoic acid induces tumor cell death, unlike single agents.
  • Identifying the molecular mechanisms behind this combined therapy is crucial.

Purpose of the Study:

  • To elucidate the molecular basis of IFN/all-trans-retinoic acid-induced tumor cell death.
  • To identify gene products mediating this cell death pathway.
  • To define the functional role of thioredoxin reductase (TR) in this process.

Main Methods:

  • Antisense knockout approach to identify death-mediating genes (GRIMs).
  • Isolation and characterization of GRIM cDNAs, including GRIM-12 (TR).
  • Generation of thioredoxin reductase (TR) mutants to study caspase-dependent cell death.

Main Results:

  • GRIM-12 was identified as human thioredoxin reductase (TR).
  • Wild-type TR activated cell death, which was inhibited by caspase inhibitors.
  • A catalytically inactive TR mutant inhibited caspase 8-induced cell death and cytochrome c release.
  • TR modulates caspase 8 activity and stimulates death receptor gene expression.

Conclusions:

  • Thioredoxin reductase (TR) plays a key role in IFN/all-trans-retinoic acid-induced tumor cell death.
  • TR promotes cell death by modulating caspase 8 activity and death receptor expression.
  • This study reveals a novel cell death regulation mechanism involving redox enzymes and combination therapy.

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