THIOREDOXIN REDUCTASE MEDIATES CELL-DEATH EFFECTS OF THE COMBINATION OF BETA-INTERFERON AND RETINOIC ACID

Interferons (IFNs) and retinoids are potent biological response modifi ers. By using JAK-STAT pathways, IFNs regulate the expression of genes involved in antiviral, antitumor, and immunomodulatory actions, Retin oids exert their cell growth-regulatory effects via nuclear receptors, which also function as transcription factors. Although these ligands act through distinct mechanisms, several studies have shown that the c ombination of IFNs and retinoids synergistically inhibits cell growth. We have previously reported that IFN-beta-all-trans-retinoic acid (RA ) combination is a more potent growth suppressor of human tumor xenogr afts in vivo than either agent alone. Furthermore, the IFN-RA combinat ion causes cell death in several tumor cell lines in vitro. However, t he molecular basis for these growth-suppressive actions is unknown. It has been suggested that certain gene products, which mediate the anti viral actions of IFNs, are also responsible for the antitumor actions of the IFN-RA combination, However, we did not find a correlation betw een their activities and cell death. Therefore, we have used an antise nse knockout approach to directly identify the gene products that medi ate cell death and have isolated several genes associated with retinoi d-IFN-induced mortality (GRIM), In this investigation, we characterize d one of the GRIM cDNAs, GRIM-12, Sequence analysis suggests that the GRIM-12 product is identical to human thioredoxin reductase (TR), TR i s posttranscriptionally induced by the IFN-RA combination in human bre ast carcinoma cells. Overexpression of GRIM-12 causes a small amount o f cell death and further enhances the susceptibility of cells to IFN-R A-induced death. Dominant negative inhibitors directed against TR inhi bit its cell death-inducing functions. Interference with TR enzymatic activity led to growth promotion in the presence of the IFN-RA combina tion. Thus, these studies identify a novel function for TR in cell gro wth regulation.