The interferon-beta and tamoxifen combination induces apoptosis using thioredoxin reductase.
Interferons (IFNs) suppress cell growth by inducing cellular genes. The anti-estrogen tamoxifen (Tam), binds to estrogen receptor and inhibits transcription of estrogen stimulated genes. In cells resistant to IFN-induced growth suppression, IFN/Tam combination causes cell death. We previously reported that the combination of IFN-beta and Tam was a more potent growth suppressor of human tumor xenografts than either agent alone. The IFN/Tam combination acts in a manner similar to the IFN/retinoic acid combination. Using a genetic technique, we have recently identified several genes associated with retinoid-IFN-induced mortality (GRIM). One such gene, GRIM-12, was identical to human thioredoxin reductase (TR). In the present study we have examined whether the IFN/Tam combination also requires GRIM-12 for inducing cell death. We report here that GRIM-12 is necessary for mediating the cell death 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 expression or by dominant negative inhibitors caused resistance to IFN/Tam induced death and promoted cell growth. Overexpression of GRIM-12 increased IFN/Tam induced apoptosis. Thus, these studies have identified a critical role for GRIM-12 (TR) in apoptosis.
Lindner
D J
DJ
Center for Cancer Drug Development, Taussig Cancer Center, Lerner Research Institute, Cleveland Clinic Foundation, Cleveland, OH, USA. lindned@cc.ccf.org
Hofmann
E R
ER
Karra
S
S
Kalvakolanu
D V
DV
D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects*; D001943:Breast Neoplasms; D002455:Cell Division / Q000187:drug effects; D016373:DNA, Antisense; D004357:Drug Synergism; D004722:Endoribonucleases / Q000378:metabolism; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005822:Genetic Vectors; D006801:Humans; D016899:Interferon-beta / Q000494:pharmacology*; D051379:Mice; D010051:Ovarian Neoplasms; D013629:Tamoxifen / Q000494:pharmacology*; D013880:Thioredoxin-Disulfide Reductase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D016373:DNA, Antisense; D013629:Tamoxifen; D016899:Interferon-beta; D013880:Thioredoxin-Disulfide Reductase; D004722:Endoribonucleases; C031956:2-5A-dependent ribonuclease