Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.
Combined inhibition of p97 and the proteasome causes lethal disruption of the secretory apparatus in multiple myeloma cells.
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DOI：
10.1371/journal.pone.0074415
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Dillon N
中科院分区：
文献类型：
--
作者：
Auner HW;Moody AM;Ward TH;Kraus M;Milan E;May P;Chaidos A;Driessen C;Cenci S;Dazzi F;Rahemtulla A;Apperley JF;Karadimitris A;Dillon N
抑制蛋白酶体是治疗多发性骨髓瘤的一种广泛使用的策略，它利用了多发性骨髓瘤细胞（MMCs）必须处理的大量分泌负荷。MMCs对蛋白酶体抑制的抗性与蛋白酶体内质网（ER）相关降解（ERAD）的不完全破坏和非蛋白酶体蛋白质降解途径的激活有关。atp酶p97 （VCP/Cdc48）在介导ERAD和非蛋白酶体蛋白降解中起关键作用，可以通过小分子抑制在药理学上靶向。在本研究中，我们比较了eyarestatin 1和DBeQ抑制p97对MMCs分泌器官的影响与蛋白酶体抑制剂硼替佐米的影响，以及p97和蛋白酶体联合抑制的影响。我们发现p97抑制引起的细胞反应与蛋白酶体抑制引起的细胞反应不同，并且在MMC系之间的反应差异很大。此外，我们发现p97和蛋白酶体的双重抑制最终破坏了MMCs的内质网结构和细胞内蛋白质代谢。在我们分析的所有MMC细胞系中，包括硼替佐米适应的AMO-1细胞，p97和蛋白酶体的双重抑制诱导了高水平的凋亡，并且也有效地杀死了原代MMC。仅在未转化和非分泌细胞中观察到轻微毒性。我们的观察结果强调了p97和蛋白酶体在维持MMCs分泌稳态中的非冗余作用，并为p97和蛋白酶体的双重靶向治疗作为多发性骨髓瘤的潜在新治疗策略提供了临床前概念框架。
Inhibition of the proteasome is a widely used strategy for treating multiple myeloma that takes advantage of the heavy secretory load that multiple myeloma cells (MMCs) have to deal with. Resistance of MMCs to proteasome inhibition has been linked to incomplete disruption of proteasomal endoplasmic-reticulum (ER)-associated degradation (ERAD) and activation of non-proteasomal protein degradation pathways. The ATPase p97 (VCP/Cdc48) has key roles in mediating both ERAD and non-proteasomal protein degradation and can be targeted pharmacologically by small molecule inhibition. In this study, we compared the effects of p97 inhibition with Eeyarestatin 1 and DBeQ on the secretory apparatus of MMCs with the effects induced by the proteasome inhibitor bortezomib, and the effects caused by combined inhibition of p97 and the proteasome. We found that p97 inhibition elicits cellular responses that are different from those induced by proteasome inhibition, and that the responses differ considerably between MMC lines. Moreover, we found that dual inhibition of both p97 and the proteasome terminally disrupts ER configuration and intracellular protein metabolism in MMCs. Dual inhibition of p97 and the proteasome induced high levels of apoptosis in all of the MMC lines that we analysed, including bortezomib-adapted AMO-1 cells, and was also effective in killing primary MMCs. Only minor toxicity was observed in untransformed and non-secretory cells. Our observations highlight non-redundant roles of p97 and the proteasome in maintaining secretory homeostasis in MMCs and provide a preclinical conceptual framework for dual targeting of p97 and the proteasome as a potential new therapeutic strategy in multiple myeloma.
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