The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase

Interferons (IFNs) suppress cell growth by inducing cellular genes. The ant i-estrogen tamoxifen (Tam), binds to estrogen receptor and inhibits transcr iption of estrogen stimulated genes. In cells resistant to IFN-induced grow th suppression, EFN/Tam combination causes cell death. We previously report ed that the combination of IFN-beta and Tam was a more potent growth suppre ssor of human tumor xenografts than either agent alone. The IFN/Tam combina tion acts in a manner similar to the IFN/retinoic acid combination. Using a genetic technique, we have recently identified several genes associated wi th retinoid-IFN-induced mortality (GRIM). One such gene, GRIM-12, was ident ical to human thioredoxin reductase (TR). In the present study we have exam ined whether the IFN/Tam combination also requires GRIM-12 for inducing cel l death. We report here that GRIM-12 is necessary for mediating the cell de ath effects of IFN/Tam, and its expression is induced by IFN/Tam, at a post -transcriptional stage. Repression of GRIM-12 levels either by antisense ex pression or by dominant negative inhibitors caused resistance to IFN/Tam in duced death and promoted cell growth. Overexpression of GRIM-1I2 increased IFN/Tam induced apaptosis. Thus, these studies have identified a critical r ole for GRIM-12 (IR) in apoptosis. (C) 2000 Elsevier Science B.V. All right s reserved.