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Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination

X Ma1, S Karra, D J Lindner

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

Oncogene
|July 6, 2001
PubMed

Insights

Interferons (IFNs) and retinoids induce tumor cell death by activating thioredoxin reductase (TR). Thioredoxin (Trx) plays a key role in this TR-mediated cell death pathway, influencing caspase-8 activation.

Area of Science:

  • Oncology
  • Cell Biology
  • Biochemistry

Background:

  • Interferons (IFNs) and retinoids are known tumor growth suppressors.
  • Previous studies showed that a combination of IFN-beta and all-trans retinoic acid (RA) induces tumor cell death, unlike single agents.
  • A genetic screen identified Genes associated with Retinoid-IFN induced Mortality (GRIM) crucial for this cell death.

Purpose of the Study:

  • To investigate the role of thioredoxin reductase (TR) and its downstream substrate, thioredoxin (Trx), in the cell death pathway induced by the IFN/RA combination.
  • To elucidate the mechanism by which TR and Trx regulate IFN/RA-induced apoptosis.

Main Methods:

  • Genetic screening to identify GRIM genes, including TR.
  • Manipulation of thioredoxin expression using antisense RNA and overexpression of wildtype and mutant Trx1.
  • Assays to evaluate cell death and caspase activation (caspase-8 and caspase-3).

Main Results:

  • GRIM-12 was identified as human thioredoxin reductase (TR), an enzyme regulating intracellular redox state.
  • Inhibition of thioredoxin expression or use of a redox-inactive Trx1 mutant suppressed IFN/RA-induced cell death.
  • Overexpression of wildtype thioredoxin augmented cell death, partly via caspase-8 activation.

Conclusions:

  • The IFN/RA combination induces tumor cell death through a novel pathway involving redox enzymes, specifically TR and Trx.
  • Thioredoxin's redox activity is critical for mediating cell death, influencing caspase-8 activation in this pathway.
  • These findings reveal a new mechanism of apoptosis regulation by the combination of interferons and retinoids.

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