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

Multiple myeloma (MM) remains incurable due to drug resistance. Ribosomal protein S3 (RPS3) has been identified as a non-Rel subunit of NF-?B. 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 delayed the survival of MM tumour-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 PKCd, which played an important role in activating the canonical NF-?B signalling and inducing cell survival and drug resistance in MM. Notably, the inhibition of NF-?B signalling 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. Overall design: To investigate the mechanism of TRIP13 in multiple myeloma (MM), we established ARP-1 MM cells stably transfected with TRIP13 overexpression (TRIP13-OE) and empty vector (EV).We then performed RNA-seq analysis on three independent groups of TRIP13 OE ARP-1 cells and corresponding EV cells. Comparative gene expression profiling analysis of RNA-seq data for TRIP13-OE and its corresponding EV ARP-1 MM cells.