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

Oncogene volume 20, pages 3703–3715 (2001)Cite this article

An Erratum to this article was published on 19 October 2001

Abstract

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-β and all-trans retinoic acid combination, but not the single agents, induces death in several tumor cell lines. Employing a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effect of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox state. To define the participants of TR mediated death pathway we have examined the role of thioredoxin (Trx), its downstream substrate, and its influence on IFN/RA-induced death regulation. Inhibition of the thioredoxin expression by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacking the critical cysteine residues blocked cell death. In contrast, overexpression of wildtype thioredoxin augmented cell death. This effect of Trx1 was in part due to its ability to augment cell death via caspase-8. The redox inactive Trx1 mutant inhibits the cell death induced by caspase-8 but not caspase-3. These studies identify a novel mechanism of cell death regulation by IFN/RA combination involving redox enzymes.

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Abbreviations

FLIP:

FLICE-inhibitory protein

GRIM:

Genes associated with Retinoid-IFN induced mortality

IFN:

Interferon

JAK:

Janus tyrosine kinase

RA:

all trans retinoic acid

SRB:

Sulforhodamine B

STAT:

Signal transducing activator of transcription

TR:

thioredoxin reductase

Trx:

thioredoxin

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Acknowledgements

These studies are supported by the National Cancer Institute grants CA 78282 and CA 71401 to DV Kalvakolanu and National Institutes of Health grant HL-58122 to SPM Reddy. We thank E Alnemri, and J Tschopp, for providing plasmids used in this study.

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Author notes

  1. Daniel J Lindner

    Present address: Taussig Cancer Center, Cleveland Clinic Foundation, Cleveland, 44195, Ohio, OH, USA

  2. Xinrong Ma and Sreenivasu Karra: X Ma and S Karra contributed equally to this work

Authors and Affiliations

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

    Xinrong Ma, Sreenivasu Karra, Daniel J Lindner, Junbo Hu & Dhananjaya D Kalvakolanu

  2. Department of Environmental Sciences, The Johns Hopkins University School of Public Health, Baltimore, MD, Maryland, USA

    Sekhar PM Reddy

  3. Department of Molecular Genetics and Virology, Weizmann Institute of Science, Rehovot, Israel

    Adi Kimchi

  4. Department of Biological Responses, Institute for Virus Research, 53 Kawahara-Cho, Shogin, Japan

    Junji Yodoi

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Ma, X., Karra, S., Lindner, D. et al. Thioredoxin participates in a cell death pathway induced by interferon and retinoid combination. Oncogene 20, 3703–3715 (2001). https://doi.org/10.1038/sj.onc.1204477

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