蛋白酶体
活力测定
硼替佐米
泛素
蛋白酶体抑制剂
生物
细胞凋亡
癌症研究
细胞生物学
细胞生长
细胞周期检查点
细胞周期
分子生物学
化学
多发性骨髓瘤
免疫学
生物化学
基因
作者
Ting Du,Yan Song,Arghya Ray,Yao Yao,Mehmet K. Samur,Chen Shen,Johany Penailillo,Tomasz Sewastianik,Yu‐Tzu Tai,Mariateresa Fulciniti,Nikhil C. Munshi,Hao Wu,Ruben D. Carrasco,Dharminder Chauhan,Kenneth C. Anderson,Xueping Wan
出处
期刊:Blood
[American Society of Hematology]
日期:2023-01-11
被引量:2
标识
DOI:10.1182/blood.2022017897
摘要
PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the 26S proteasome. Because proteasome inhibition is a common therapeutic strategy in multiple myeloma (MM), we investigated Rpn10 and found that it is highly expressed in MM cells compared with normal plasma cells. Rpn10 levels inversely correlated with overall survival in patients with MM. Inducible knockout or knockdown of Rpn10 decreased MM cell viability both in vitro and in vivo by triggering the accumulation of polyubiquitinated proteins, cell cycle arrest, and apoptosis associated with the activation of caspases and unfolded protein response-related pathways. Proteomic analysis revealed that inhibiting Rpn10 increased autophagy, antigen presentation, and the activation of CD4+ T and natural killer cells. We developed an in vitro AlphaScreen binding assay for high-throughput screening and identified a novel Rpn10 inhibitor, SB699551 (SB). Treating MM cell lines, leukemic cell lines, and primary cells from patients with MM with SB decreased cell viability without affecting the viability of normal peripheral blood mononuclear cells. SB inhibited the proliferation of MM cells even in the presence of the tumor-promoting bone marrow milieu and overcame proteasome inhibitor (PI) resistance without blocking the 20S proteasome catalytic function or the 19S deubiquitinating activity. Rpn10 blockade by SB triggered MM cell death via similar pathways as the genetic strategy. In MM xenograft models, SB was well tolerated, inhibited tumor growth, and prolonged survival. Our data suggest that inhibiting Rpn10 will enhance cytotoxicity and overcome PI resistance in MM, providing the basis for further optimization studies of Rpn10 inhibitors for clinical application.
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