Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2.
Role of NF-kappaB in the rescue of multiple myeloma cells from glucocorticoid-induced apoptosis by bcl-2.
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DOI：
10.1182/blood.v93.9.3044
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发表时间：
1999-05
期刊：
影响因子：
20.3
通讯作者：
R. Feinman;J. Koury;M. Thames;B. Barlogie;J. Epstein;D. Siegel
中科院分区：
文献类型：
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作者：
R. Feinman;J. Koury;M. Thames;B. Barlogie;J. Epstein;D. Siegel
多发性骨髓瘤（MM）细胞逃避糖皮质激素诱导的细胞凋亡的分子机制尚未阐明。使用人 IgAkappa MM 细胞系 (ARP-1)，我们发现地塞米松 (Dex) 诱导的细胞凋亡与 NF-kappaB DNA 结合和 kappaB 依赖性转录减少有关。通过 Supershift 电泳迁移率变动分析 (EMSA) 在 ARP-1 细胞中检测到核 p50:p50 和 p50:p65 NF-kappaB 复合物。 Dex 介导的对 NF-kappaB DNA 结合的抑制先于膜联蛋白 V 结合的显着增加，从而表明 NF-kappaB 活性的减弱是 Dex 诱导细胞凋亡的早期事件。 ARP-1 细胞中 bcl-2 的过度表达可防止 Dex 介导的 NF-kappaB 活性抑制和细胞凋亡。在两种先前鉴定的 Dex 抗性 MM 细胞系（RPMI8226 和 ARH-77）中也观察到持续的 NF-kappaB DNA 结合，这些细胞系表达中等水平的内源性 bcl-2 和 IkappaBalpha 蛋白。此外，在 ARP-1 细胞中强制表达 bcl-2 并不能阻止 Dex 对 IkappaBalpha 蛋白的增强。我们还注意到，新鲜获得的原发性骨髓瘤细胞中 Dex 介导的 NF-κB 下调与患者对糖皮质激素化疗的反应之间可能存在关联。总的来说，我们的数据表明 bcl-2 在 MM 细胞中的保护作用作用于 NF-kappaB 激活信号通路的上游，并且 NF-kappaB 作为进行性 MM 的生物标志物的潜在用途。
The molecular mechanisms by which multiple myeloma (MM) cells evade glucocorticoid-induced apoptosis have not been delineated. Using a human IgAkappa MM cell line (ARP-1), we found that dexamethasone (Dex)-induced apoptosis is associated with decreased NF-kappaB DNA binding and kappaB-dependent transcription. Both nuclear p50:p50 and p50:p65 NF-kappaB complexes are detected in ARP-1 cells by supershift electrophoretic mobility shift assay (EMSA). Dex-mediated inhibition of NF-kappaB DNA binding precedes a notable increase in annexin V binding, thereby indicating that diminished NF-kappaB activity is an early event in Dex-induced apoptosis. Overexpression of bcl-2 in ARP-1 cells prevents Dex-mediated repression of NF-kappaB activity and apoptosis. Sustained NF-kappaB DNA binding is also observed in two previously characterized Dex-resistant MM cell lines (RPMI8226 and ARH-77) that express moderate levels of endogenous bcl-2 and IkappaBalpha proteins. In addition, enforced bcl-2 expression in ARP-1 cells did not prevent the augmentation of IkappaBalpha protein by Dex. We also noted a possible association between Dex-mediated downregulation of NF-kappaB in freshly obtained primary myeloma cells and the patients' responsiveness to glucocorticoid-based chemotherapy. Collectively, our data suggest that the protective effects of bcl-2 in MM cells act upstream in the NF-kappaB activation-signaling pathway and the potential use of NF-kappaB as a biomarker in progressive MM.