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

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

Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta 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 associat...

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Bibliographic Details
Published in:Oncogene Vol. 20; no. 28; pp. 3703 - 3715
Main Authors: XINRONG MA, KARRA, Sreenivasu, LINDNER, Daniel J, JUNBO HU, REDDY, Sekhar P. M, KIMCHI, Adi, JUNJI YODOI, KALVAKOLANU, Dhananjaya D
Format: Journal Article
Language:English
Published: Basingstoke Nature Publishing 21-06-2001
Nature Publishing Group
Subjects:
Ageing, cell death
Antineoplastic Agents - metabolism
Antineoplastic Agents - pharmacology
Antisense RNA
Apoptosis
Biological and medical sciences
Caspase 8
Caspase 9
Caspase-3
Caspases - metabolism
Cell Death
Cell physiology
Down-Regulation
Enzyme Activation
Fundamental and applied biological sciences. Psychology
Gene Expression
Humans
Interferon-beta - metabolism
Interferon-beta - pharmacology
Molecular and cellular biology
Mutants
redox enzymes
Redox properties
Retinoic acid
Retinoids
Signal Transduction
Thioredoxin
Thioredoxins - genetics
Thioredoxins - metabolism
Transfection
Tretinoin - metabolism
Tretinoin - pharmacology
Tumor cell lines
Tumor Cells, Cultured
Tumors
β-Interferon
Human
Peptidases
Cell line
Enzyme
Cytokine
Beta interferon
Retinoid
Caspase
Hydrolases
Mammary gland
Thioredoxin
Apoptosis
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Summary:Interferons (IFNs) and retinoids are potent tumor growth suppressors. We have shown earlier that the IFN-beta 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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ISSN:0950-9232
1476-5594
DOI:10.1038/sj.onc.1204477