硼替佐米治疗多发性骨髓瘤:去泛素化酶Rpn11抑制剂,克服耐药性

Oncogene

2017-06-05Article

7.519

影响因子

原标题:阻断去泛素化酶Rpn11,引发多发性骨髓瘤细胞凋亡、克服硼替佐米的耐药性

① 蛋白酶体抑制是治疗多发性骨髓瘤的有效方法,但时常需要新的治疗策略来克服蛋白酶体抑制剂的耐药性;② 该研究针对蛋白酶体20S上游的去泛素化酶Rpn11是否克服蛋白酶体抑制剂的耐药性进行了实验;③ 通过基因表达分析,多发性骨髓瘤患者骨髓免疫组化研究,反转录PCR和蛋白质分析等方式展开研究;④ 临床前数据为蛋白酶体20S上游的去泛素化酶Rpn11增强细胞毒性和克服蛋白酶体抑制剂耐药提供了理论基础。

去泛素化酶Rpn11 多发性骨髓瘤 耐药性

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Title:
Blockade of deubiquitylating enzyme Rpn11 triggers apoptosis in multiple myeloma cells and overcomes bortezomib resistance

DOI:
10.1038/onc.2017.172

Abstract & Authors展开

Abstract:
Proteasome inhibition is an effective therapy for multiple myeloma (MM) patients; however, the emergence of drug resistance is common. Novel therapeutic strategies to overcome proteasome inhibitor resistance are needed. In this study, we examined whether targeting deubiquitylating (DUB) enzymes upstream of 20S proteasome overcomes proteasome inhibitor resistance. Gene expression analysis, immunohistochemical studies of MM patient bone marrow, reverse transcription-PCR and protein analysis show that Rpn11/POH1, a DUB enzyme upstream of 20S proteasome, is more highly expressed in patient MM cells than in normal plasma cells. Importantly, Rpn11 expression directly correlates with poor patient survival. Loss-of-function studies show that Rpn11-siRNA knockdown decreases MM cell viability. Pharmacological inhibition of Rpn11 with O-phenanthroline (OPA) blocks cellular proteasome function, induces apoptosis in MM cells and overcomes resistance to proteasome inhibitor bortezomib. Mechanistically, Rpn11 inhibition in MM cells activates caspase cascade and endoplasmic stress response signaling. Human MM xenograft model studies demonstrate that OPA treatment reduces progression of tumor growth and prolongs survival in mice. Finally, blockade of Rpn11 increases the cytotoxic activity of anti-MM agents lenalidomide, pomalidomide or dexamethasone. Overall, our preclinical data provide the rationale for targeting DUB enzyme Rpn11 upstream of 20S proteasome to enhance cytotoxicity and overcome proteasome inhibitor resistance in MM.Oncogene advance online publication, 5 June 2017; doi:10.1038/onc.2017.172.

All Authors:
Y Song,S Li,A Ray,D S Das,J Qi,M K Samur,Y-T Tai,N Munshi,R D Carrasco,D Chauhan,K C Anderson

First Authors:
D Chauhan,K C Anderson

Correspondence:
D Chauhan,K C Anderson

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