Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells.
Targeting HSP90 and monoclonal protein trafficking modulates the unfolded protein response, chaperone regulation and apoptosis in myeloma cells.
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DOI：
10.1038/bcj.2013.64
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发表时间：
2013-12-06
影响因子：
12.8
通讯作者：
Holstein, S. A.
中科院分区：
文献类型：
--
作者：
Born, E. J.;Hartman, S. V.;Holstein, S. A.
多发性骨髓瘤的特征在于产生大量的单克隆蛋白。我们以前已经证明，选择类异戊二烯生物合成途径（IBP）的抑制剂诱导骨髓瘤细胞的凋亡，通过抑制Rab香叶基香叶基化，导致单克隆蛋白质运输和未折叠蛋白反应（UPR）途径的诱导中断。热休克蛋白90（HSP 90）抑制剂破坏蛋白质折叠，目前正在骨髓瘤的临床研究中。在单克隆蛋白产生细胞中研究了IBP和HSP 90抑制剂组合对细胞死亡、单克隆蛋白运输、UPR和伴侣调节的影响。在用IBP和HSP 90抑制剂处理后观察到细胞死亡的增强诱导，这通过ER应激和非ER应激途径发生。HSP 90抑制剂17-AAG消除了IBP抑制剂对骨髓瘤细胞内单克隆蛋白水平和定位以及诱导UPR的影响。在骨髓瘤与淀粉样轻链细胞中观察到对伴侣蛋白表达的不同影响。在这里，我们证明了新的策略，针对MP贩运音乐会与HSP 90增强骨髓瘤细胞死亡，通过一个复杂的调制的ER压力，UPR，和细胞死亡途径。
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.
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