核糖体蛋白 S3 介导蛋白酶体抑制剂耐药性：多发性骨髓瘤潜在的治疗应用。

Ribosomal protein S3 mediates drug resistance of proteasome inhibitor: potential therapeutic application in multiple myeloma.

机构信息

Department of Hematology, Shanghai East Hospital, Tongji University School of Medicine, Shanghai 200120.

Department of Hematology, Shanghai Tenth People's Hospital, Tongji University School of Medicine, Shanghai 200072.

出版信息

Haematologica. 2024 Apr 1;109(4):1206-1219. doi: 10.3324/haematol.2023.282789.

DOI:10.3324/haematol.2023.282789

PMID:37767568

原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC10985453/

Abstract

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-κB. However, the detailed biological roles of RPS3 remain unclear. Here, we report for the first time that RPS3 is necessary for MM survival and drug resistance. RPS3 was highly expressed in MM, and knockout of RPS3 in MM inhibited cell growth and induced cell apoptosis both in vitro and in vivo. Overexpression of RPS3 mediated the proteasome inhibitor resistance of MM and shortened the survival of MM tumor-bearing animals. Moreover, our present study found an interaction between RPS3 and the thyroid hormone receptor interactor 13 (TRIP13), an oncogene related to MM tumorigenesis and drug resistance. We demonstrated that the phosphorylation of RPS3 was mediated by TRIP13 via PKCδ, which played an important role in activating the canonical NF-κB signaling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-κB signaling by the small-molecule inhibitor targeting TRIP13, DCZ0415, was capable of triggering synergistic cytotoxicity when combined with bortezomib in drug-resistant MM. This study identifies RPS3 as a novel biomarker and therapeutic target in MM.

摘要

多发性骨髓瘤（MM）仍然无法治愈，这是由于耐药性所致。核糖体蛋白 S3（RPS3）已被鉴定为 NF-κB 的非 Rel 亚基。然而，RPS3 的详细生物学作用仍不清楚。在这里，我们首次报道 RPS3 是 MM 存活和耐药所必需的。RPS3 在 MM 中高度表达，在体外和体内敲除 RPS3 均可抑制 MM 细胞的生长并诱导细胞凋亡。RPS3 的过表达介导了 MM 对蛋白酶体抑制剂的耐药性，并缩短了 MM 荷瘤动物的存活时间。此外，我们目前的研究发现 RPS3 与甲状腺激素受体相互作用蛋白 13（TRIP13）之间存在相互作用，TRIP13 是一种与 MM 肿瘤发生和耐药性相关的癌基因。我们证明 RPS3 的磷酸化是由 TRIP13 通过 PKCδ 介导的，这在激活经典 NF-κB 信号通路以及诱导 MM 细胞存活和耐药性方面发挥着重要作用。值得注意的是，靶向 TRIP13 的小分子抑制剂 DCZ0415 抑制 NF-κB 信号通路，与硼替佐米联合使用时，可在耐药性 MM 中引发协同细胞毒性作用。这项研究确定了 RPS3 是 MM 的一种新的生物标志物和治疗靶点。