CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：Ubiquitin receptor PSMD4/Rpn10 is a novel therapeutic target in multiple myeloma.
Ubiquitin receptor PSMD4/Rpn10 is a novel therapeutic target in multiple myeloma.
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PSMD4/Rpn10 是 19S 蛋白酶体复合物的一个亚基，参与将靶蛋白送入 26S 蛋白酶体的催化机制中。由于蛋白酶体抑制是多发性骨髓瘤（MM）中常见的治疗策略，我们研究了 Rpn10，并发现其与正常浆细胞相比在 MM 细胞中高表达。Rpn10 水平与 MM 患者的总生存期呈负相关。诱导性敲除或敲低 Rpn10 可通过触发多泛素化蛋白的积累、细胞周期阻滞以及与 caspase 和未折叠蛋白反应相关通路激活相关的凋亡，在体外和体内降低 MM 细胞活力。蛋白质组学分析显示，抑制 Rpn10 可增加自噬、抗原呈递以及 CD4+ T 细胞和NK 细胞的激活。
我们开发了一种用于高通量筛选的体外 AlphaScreen 结合试验，并鉴定出一种新型 Rpn10 抑制剂 SB699551（SB）。用 SB 处理 MM 细胞系、白血病细胞系以及来自 MM 患者的原代细胞可降低细胞活力，而不影响正常外周血单个核细胞的活力。即使在存在促肿瘤骨髓微环境的情况下，SB 仍抑制 MM 细胞的增殖，并在不阻断 20S 蛋白酶体催化功能或 19S 去泛素化活性的情况下克服蛋白酶体抑制剂（PI）耐药。SB 对 Rpn10 的阻断通过类似于遗传策略的通路触发 MM 细胞死亡。在 MM 异种移植模型中，SB 耐受性良好，抑制肿瘤生长并延长生存期。
我们的数据表明，抑制 Rpn10 将增强细胞毒性并克服 MM 中的 PI 耐药，为 Rpn10 抑制剂进一步优化研究以用于临床应用提供了基础。
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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