G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells

Abstract

The effectiveness of IFN-α2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-α2b apoptosis in myeloma. In this study we assessed the effects of IFN-α2b signaling on the apoptotic activity of TRAIL and human myeloma cell survival. While TRAIL was one of the most potently induced proapoptotic genes in myeloma cells following IFN-α2b treatment, less than 20% of myeloma cells underwent apoptosis. Thus, we hypothesized that an IFN-stimulated gene (ISG) with prosurvival activity might suppress TRAIL-mediated apoptosis. Consistent with this, IFN-α2b stabilized mitochondria and inhibited caspase-3 activation, which antagonized TRAIL-mediated apoptosis and cytotoxicity after 24 hours of cotreatment in cell lines and in fresh myeloma cells, an effect not evident after 72 hours. Induced expression of G1P3, an ISG with largely unknown function, was correlated with the antiapoptotic activity of IFN-α2b. Ectopically expressed G1P3 localized to mitochondria and antagonized TRAIL-mediated mitochondrial potential loss, cytochrome c release, and apoptosis, suggesting specificity of G1P3 for the intrinsic apoptosis pathway. Furthermore, RNAimediated downregulation of G1P3 restored IFN-α2b-induced apoptosis. Our data identify the direct role of a mitochondria-localized prosurvival ISG in antagonizing the effect of TRAIL. Curtailing G1P3-mediated antiapoptotic signals could improve therapies for myeloma or other malignancies.

G1P3, an interferon- and estrogen-induced survival protein contributes to hyperplasia, tamoxifen resistance and poor outcomes in breast cancer

“…ISG signatures that may be predictive of DNA damage resistance in bronchial and breast carcinomas have been described (Einav et al, 2005;Weichselbaum et al, 2008;Luszcek et al, 2010). Supporting the potential pro-tumor activity of some ISGs, we and others identified G1P3 (ISG 6-16, IFI6), a gene robustly stimulated by IFNs, as an antiapoptotic protein (Tahara et al, 2005;Cheriyath et al, 2007).…”

“…These were the first functional insights into the cellular effects of G1P3. Consistent with its inhibitory effects on intrinsic apoptosis, G1P3 localized into the mitochondria of both myeloma and gastric cancer cells (Tahara et al, 2005;Cheriyath et al, 2007).…”

“…G1P3 antagonized intrinsic apoptosis by IFNs and tumor necrosis factor-related apoptosis-inducing ligand in myeloma cells and by 5-fluorouracil in gastric cancer cells (Tahara et al, 2005;Cheriyath et al, 2007). These were the first functional insights into the cellular effects of G1P3.…”

“…Role of the antiapoptotic factor G1P3 in breast cancer V Cheriyath et al et al, 2007), therefore, its effect on anoikis-induced mitochondrial permeability transition of MCF10A cells was investigated. Both endogenous and ectopically expressed G1P3 localized primarily into mitochondrial fractions (Figure 4a).…”

“…Role of the antiapoptotic factor G1P3 in breast cancer V Cheriyath et al et al, 2007) (Supplementary Table 4). RFS data were available for all four studies, whereas OS data were available only for three (Supplementary Table 5).…”