Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.
Blockade of Deubiquitylating Enzyme USP1 Inhibits DNA Repair and Triggers Apoptosis in Multiple Myeloma Cells.
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DOI：
10.1158/1078-0432.ccr-16-2692
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发表时间：
2017-08-01
期刊：
影响因子：
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通讯作者：
Anderson KC
中科院分区：
文献类型：
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作者：
Das DS;Das A;Ray A;Song Y;Samur MK;Munshi NC;Chauhan D;Anderson KC
泛素蛋白酶体途径是多发性骨髓瘤（MM）的有效治疗靶点。去泛素化酶USP 1参与DNA损伤反应和细胞分化途径。迄今为止，USP 1在MM生物学中的作用尚未确定。在本研究中，我们研究了USP 1在MM中的功能意义，使用遗传和生化方法。为了研究USP 1在骨髓瘤中的作用，我们使用USP 1抑制剂SJB 3 - 019 A（SJB）在骨髓瘤细胞系和患者MM细胞中进行研究。USP 1-siRNA敲低降低MM细胞活力。USP 1抑制剂SJB选择性地阻断USP 1酶活性，而不阻断其他DUB。SJB还降低MM细胞系和患者肿瘤细胞的活力，抑制骨髓浆细胞样树突状细胞诱导的MM细胞生长，并克服硼替佐米耐药性。SJB通过激活半胱天冬酶-3、半胱天冬酶-8和半胱天冬酶-9触发MM细胞的凋亡。此外，SJB降解USP 1和DNA结合蛋白的下游抑制剂，以及通过阻断范可尼贫血途径和同源重组来抑制DNA修复。SJB还下调MM干细胞更新/存活相关蛋白Notch-1、Notch-2、SOX-4和SOX-2。此外，SJB诱导产生更成熟和分化的浆细胞。SJB和HDACi ACY-1215、硼替佐米、来那度胺或泊马度胺的组合触发协同细胞毒性。我们的临床前研究为USP 1抑制剂单独或联合作为一种潜在的新型MM疗法的临床评价提供了框架。
The ubiquitin proteasome pathway is a validated therapeutic target in multiple myeloma (MM). Deubiquitylating enzyme USP1 participates in DNA damage response and cellular differentiation pathways. To date, the role of USP1 in MM biology is not defined. In the present study, we investigated the functional significance of USP1 in MM using genetic and biochemical approaches. To investigate the role of USP1 in myeloma, we utilized USP1 inhibitor SJB3-019A (SJB) for studies in myeloma cell lines and patient MM cells. USP1-siRNA knockdown decreases MM cell viability. USP1 inhibitor SJB selectively blocks USP1 enzymatic activity without blocking other DUBs. SJB also decreases the viability of MM cell lines and patient tumor cells, inhibits bone marrow plasmacytoid dendritic cells-induced MM cell growth and overcomes bortezomib-resistance. SJB triggers apoptosis in MM cells via activation of caspase-3, caspase-8 and caspase-9. Moreover, SJB degrades USP1 and downstream inhibitor of DNA binding proteins, as well as inhibits DNA repair via blockade of Fanconi anemia pathway and homologous recombination. SJB also downregulates MM stem cell renewal/survival-associated proteins Notch-1, Notch-2, SOX-4 and SOX-2. Moreover, SJB induced generation of more mature and differentiated plasma cells. Combination of SJB and HDACi ACY-1215, bortezomib, lenalidomide, or pomalidomide triggers synergistic cytotoxicity. Our preclinical studies provide the framework for clinical evaluation of USP1 inhibitors, alone or in combination, as a potential novel MM therapy.