Thioredoxin participates in a cell death pathway induced by interferon andretinoid combination

Interferons (IFNs) and retinoids are potent tumor growth suppressors, We ha ve shown earlier that the IFN-P and all-trans retinoic acid combination, bu t not the single agents, induces death in several tumor cell lines. Employi ng a genetic approach we have recently identified several Genes associated with Retinoid-IFN induced Mortality (GRIM) that mediate the cell death effe ct of IFN/RA combination. One of the GRIMs, GRIM-12, was identical to human thioredoxin reductase (TR), an enzyme that controls intracellular redox st ate. To define the participants of TR mediated death pathway we have examin ed the role of thioredoxin (Trx), its downstream substrate, and its influen ce on IFN/RA-induced death regulation. Inhibition of the thioredoxin expres sion by antisense RNA suppressed cell death. Similarly, a mutant Trx1 lacki ng the critical cysteine residues blocked cell death. In contrast, overexpr ession of wildtype thioredoxin augmented cell death. This effect of Trx1 wa s 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 regulatio n by IFN/RA combination involving redox enzymes.