文章：

靶向HSP90和单克隆蛋白转运可调节骨髓瘤细胞的未折叠蛋白应答、伴侣蛋白调控和凋亡

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells

原文发布日期：2013-12-06

DOI: 10.1038/bcj.2013.64

类型: Original Article

开放获取: 是

英文摘要：

Multiple myeloma is characterized by the production of substantial quantities of monoclonal protein. We have previously demonstrated that select inhibitors of the isoprenoid biosynthetic pathway (IBP) induce apoptosis of myeloma cells via inhibition of Rab geranylgeranylation, leading to disruption of monoclonal protein trafficking and induction of the unfolded protein response (UPR) pathway. Heat-shock protein 90 (HSP90) inhibitors disrupt protein folding and are currently under clinical investigation in myeloma. The effects of combining IBP and HSP90 inhibitors on cell death, monoclonal protein trafficking, the UPR and chaperone regulation were investigated in monoclonal protein-producing cells. An enhanced induction of cell death was observed following treatment with IBP and HSP90 inhibitors, which occurred through both ER stress and non-ER stress pathways. The HSP90 inhibitor 17-AAG abrogated the effects of the IBP inhibitors on intracellular monoclonal protein levels and localization as well as induction of the UPR in myeloma cells. Disparate effects on chaperone expression were observed in myeloma vs amyloid light chain cells. Here we demonstrate that the novel strategy of targeting MP trafficking in concert with HSP90 enhances myeloma cell death via a complex modulation of ER stress, UPR, and cell death pathways.

摘要翻译： 

多发性骨髓瘤的特征是产生大量单克隆蛋白。我们先前已证明，类异戊二烯生物合成途径的选择性抑制剂可通过抑制Rab蛋白的香叶基香叶基化，诱导骨髓瘤细胞凋亡，进而破坏单克隆蛋白运输并激活未折叠蛋白反应通路。热休克蛋白90抑制剂可干扰蛋白质折叠，目前正在骨髓瘤领域进行临床研究。本研究在单克隆蛋白生成细胞中探讨了IBP抑制剂与HSP90抑制剂联用对细胞死亡、单克隆蛋白运输、UPR及分子伴侣调控的影响。联合使用IBP与HSP90抑制剂可通过内质网应激和非内质网应激双重途径显著增强细胞死亡诱导效应。HSP90抑制剂17-AAG能逆转IBP抑制剂对骨髓瘤细胞内单克隆蛋白水平、定位及UPR诱导的影响。在骨髓瘤细胞与轻链淀粉样蛋白细胞中观察到分子伴侣表达的差异性调控。本研究证实，靶向单克隆蛋白运输联合HSP90抑制的新策略，能通过复杂调控内质网应激、UPR及细胞死亡通路来增强骨髓瘤细胞死亡。

原文链接：

Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells