Cheriyath Venugopalan, Glaser Keith B, Waring Jeffrey F, Baz Rachid, Hussein Mohamad A, Borden Ernest C
Center for Hematology and Oncology Molecular Therapeutics, The Cleveland Clinic, Taussig Cancer Center, Cleveland, Ohio, USA.
J Clin Invest. 2007 Oct;117(10):3107-17. doi: 10.1172/JCI31122.
The effectiveness of IFN-alpha2b for human multiple myeloma has been variable. TRAIL has been proposed to mediate IFN-alpha2b apoptosis in myeloma. In this study we assessed the effects of IFN-alpha2b 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-alpha2b 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-alpha2b 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-alpha2b. 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-alpha2b-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.
干扰素α2b对人类多发性骨髓瘤的疗效不一。肿瘤坏死因子相关凋亡诱导配体（TRAIL）被认为可介导干扰素α2b诱导的骨髓瘤细胞凋亡。在本研究中，我们评估了干扰素α2b信号传导对TRAIL凋亡活性及人类骨髓瘤细胞存活的影响。虽然TRAIL是干扰素α2b处理后骨髓瘤细胞中最显著诱导的促凋亡基因之一，但不到20%的骨髓瘤细胞发生凋亡。因此，我们推测具有促存活活性的干扰素刺激基因（ISG）可能会抑制TRAIL介导的凋亡。与此一致的是，干扰素α2b可稳定线粒体并抑制半胱天冬酶-3激活，在细胞系和新鲜骨髓瘤细胞中共处理24小时后，这会拮抗TRAIL介导的凋亡和细胞毒性，而72小时后这种作用不明显。功能 largely未知的ISG G1P3的诱导表达与干扰素α2b的抗凋亡活性相关。异位表达的G1P3定位于线粒体，并拮抗TRAIL介导的线粒体膜电位丧失、细胞色素c释放及凋亡，提示G1P3对内在凋亡途径具有特异性。此外，RNA干扰介导的G1P3下调可恢复干扰素α2b诱导的凋亡。我们的数据确定了一种定位于线粒体的促存活ISG在拮抗TRAIL作用中的直接作用。减少G1P3介导的抗凋亡信号可能会改善骨髓瘤或其他恶性肿瘤的治疗。
