Chen Q, Gong B, Mahmoud-Ahmed A S, Zhou A, Hsi E D, Hussein M, Almasan A
Department of Cancer Biology, Lerner Research Institute, The Cleveland Clinic Foundation, Cleveland, OH 44195, USA.
Blood. 2001 Oct 1;98(7):2183-92. doi: 10.1182/blood.v98.7.2183.
It has been reported that interferons (IFNs) may have antitumor activity in multiple myeloma (MM). The mechanism for their effect on MM, however, remains elusive. This study shows that IFN-alpha and -beta, but not -gamma, induce apoptosis characterized by Annexin V positivity, nuclear fragmentation and condensation, and loss of clonogenicity in 3 MM cell lines (U266, RPMI-8266, and NCI-H929), and in plasma cells from 10 patients with MM. Apo2 ligand (Apo2L, also TRAIL) induction was one of the earliest events following IFN administration in U266 cells. Treatment of these cells with TRAIL, but not with Fas agonistic antibodies, induces apoptosis. Cell death induced by IFNs and Apo2L in U266 cells was partially blocked by a dominant-negative Apo2L receptor, DR5, demonstrating the functional significance of Apo2L induction. This study shows that IFNs activate caspases and the mitochondrial-dependent apoptotic pathway, possibly mediated by Apo2L production. Thus, IFN-alpha and -beta induce cytochrome c release from mitochondria starting at 12 hours, with an amplified release seen at 48 hours. Moreover, Bid cleavage precedes the initial cytochrome c release, whereas the late, amplified cytochrome c release coincides with changes in levels of Bcl-2, Bcl-X(L), and reduction of mitochondrial membrane potential. These results link the Apo2L induction and modulation of Bcl-2 family proteins to mitochondrial dysfunction. Furthermore, IFNs and Apo2L induce cell death of CD38(+)/CD45(-/dim) plasma cells, without significant effect on nonplasma blood cells, in a caspase and Bcl-2 cleavage-dependent manner. These results warrant further clinical studies with IFNs and Apo2L in MM.
据报道，干扰素（IFNs）可能在多发性骨髓瘤（MM）中具有抗肿瘤活性。然而，它们对MM的作用机制仍不清楚。本研究表明，IFN-α和-β而非-γ可诱导3种MM细胞系（U266、RPMI-8266和NCI-H929）以及10例MM患者浆细胞发生凋亡，其特征为膜联蛋白V阳性、核碎裂和固缩以及克隆形成能力丧失。Apo2配体（Apo2L，也称为TRAIL）诱导是IFN作用于U266细胞后最早发生的事件之一。用TRAIL而非Fas激动性抗体处理这些细胞可诱导凋亡。U266细胞中IFNs和Apo2L诱导的细胞死亡被显性负性Apo2L受体DR5部分阻断，证明了Apo2L诱导的功能意义。本研究表明，IFNs激活半胱天冬酶和线粒体依赖性凋亡途径，可能由Apo2L产生介导。因此，IFN-α和-β从12小时开始诱导细胞色素c从线粒体释放，48小时时释放量增加。此外，Bid裂解先于最初的细胞色素c释放，而后期增加的细胞色素c释放与Bcl-2、Bcl-X(L)水平变化以及线粒体膜电位降低同时发生。这些结果将Apo2L诱导和Bcl-2家族蛋白的调节与线粒体功能障碍联系起来。此外，IFNs和Apo2L以半胱天冬酶和Bcl-2裂解依赖性方式诱导CD38(+)/CD45(-/dim)浆细胞死亡，对非浆细胞血细胞无明显影响。这些结果值得对MM患者进一步开展IFNs和Apo2L的临床研究。
