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

• 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
• DOI: 10.1038/sj.onc.1204477
• EISSN: 1476-5594
• ISSN: 0950-9232

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.