Department of Medical Oncology, LeBow Institute for Myeloma Therapeutics and Jerome Lipper Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
Leukemia. 2021 Feb;35(2):550-561. doi: 10.1038/s41375-020-0865-2. Epub 2020 May 18.
Our prior study showed that inhibition of 19S proteasome-associated ubiquitin receptor Rpn13 can overcome bortezomib resistance in MM cells. Here, we performed proteomic analysis of Rpn13 inhibitor (RA190)-treated MM cells and identified an antioxidant enzyme superoxide dismutase (SOD1) as a mediator of Rpn13 signaling. SOD1 levels are higher in MM patient cells versus normal PBMCs; and importantly, SOD1 expression correlates with the progression of disease and shorter survival. Functional validation studies show that RA190-induced cytotoxicity in bortezomib-sensitive and -resistant MM cells is associated with decrease in SOD1 levels; conversely, forced expression of SOD1 inhibits RA190-induced cell death. Genetic knockdown and biochemical blockade of SOD1 with LCS-1 sensitizes bortezomib-resistant MM cells to bortezomib. SOD1 inhibitor LCS-1 decreases viability in MM cell lines and patient cells. LCS-1-induced cell death is associated with: (1) increase in superoxide and ROS levels; (2) activation of caspases, and p53/p21 signaling; (3) decrease in MCL-1, BCL, CDC2, cyclin-B1, and c-Myc; (4) ER stress response; and (5) inhibition of proteasome function. In animal model studies, LCS-1 inhibits xenografted bortezomib-resistant human MM cell growth and prolongs host survival. Our studies therefore show that targeting Rpn13 overcomes bortezomib resistance by decreasing cellular SOD1 levels, and provide the rationale for novel therapeutics targeting SOD1 to improve patient outcome in MM.
我们之前的研究表明，抑制 19S 蛋白酶体相关泛素受体 Rpn13 可以克服多发性骨髓瘤（MM）细胞对硼替佐米的耐药性。在这里，我们对 Rpn13 抑制剂（RA190）处理的 MM 细胞进行了蛋白质组学分析，鉴定出抗氧化酶超氧化物歧化酶 1（SOD1）作为 Rpn13 信号的介质。SOD1 水平在 MM 患者细胞中高于正常 PBMCs；重要的是，SOD1 的表达与疾病的进展和较短的生存期相关。功能验证研究表明，RA190 诱导硼替佐米敏感和耐药 MM 细胞的细胞毒性与 SOD1 水平的降低有关；相反，强制表达 SOD1 抑制 RA190 诱导的细胞死亡。用 LCS-1 进行 SOD1 的基因敲低和生化阻断可使硼替佐米耐药的 MM 细胞对硼替佐米敏感。SOD1 抑制剂 LCS-1 降低 MM 细胞系和患者细胞的活力。LCS-1 诱导的细胞死亡与以下因素有关：（1）超氧阴离子和 ROS 水平增加；（2）半胱天冬酶的激活，以及 p53/p21 信号通路；（3）MCL-1、BCL、CDC2、细胞周期蛋白-B1 和 c-Myc 的减少；（4）内质网应激反应；（5）蛋白酶体功能的抑制。在动物模型研究中，LCS-1 抑制异种移植的硼替佐米耐药人类 MM 细胞生长并延长宿主存活。因此，我们的研究表明，通过降低细胞内 SOD1 水平，靶向 Rpn13 克服了硼替佐米耐药性，并为靶向 SOD1 的新型治疗方法提供了依据，以改善 MM 患者的预后。
