G1P3, an IFN-induced survival factor, antagonizes TRAIL-induced apoptosis in human myeloma cells
Venugopalan Cheriyath, … , Mohamad A. Hussein, Ernest C. Borden
Venugopalan Cheriyath, … , Mohamad A. Hussein, Ernest C. Borden
Published October 1, 2007
Citation Information: J Clin Invest. 2007;117(10):3107-3117. https://doi.org/10.1172/JCI31122.
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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, RNAi-mediated 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.

Authors

Venugopalan Cheriyath, Keith B. Glaser, Jeffrey F. Waring, Rachid Baz, Mohamad A. Hussein, Ernest C. Borden

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Figure 6

Ectopic G1P3 antagonized TRAIL-induced mitochondrial perturbation.

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Ectopic G1P3 antagonized TRAIL-induced mitochondrial perturbation. (A) E...
(A) Ectopic G1P3 antagonized TRAIL-induced loss of ΔΨ. 1 × 106 HAT (left panels) or HAT-G1P3 (right panels) cells were left untreated (top panels) or treated with TRAIL (25 ng/ml) (bottom panels) for 16 hours, and ΔΨ was measured with TMRM reagent. Three independent experiments showed similar results. (B) Constitutively expressed G1P3 antagonized mitochondrial release of cytochrome c. 1 × 106 HAT (left panel) or HAT-G1P3 (right panel) cells were left untreated or treated with 25 ng/ml of TRAIL. Levels of cytochrome c in intact cells were measured with an FITC-conjugated cytochrome c antibody (histogram with thick line). Isotype-matched FITC-conjugated IgG antibody was used as a negative control (histogram with thin line). TRAIL markedly reduced the signal in HAT cells but not in HAT-G1P3 cells (filled histogram). Histograms represent results from 1 of 2 independent experiments.