Ubiquitin receptor PSMD4/Rpn10 is a novel therapeutic target in multiple myeloma
Description
Abstract: PSMD4/Rpn10 is a subunit of the 19S proteasome unit that is involved with feeding target proteins into the catalytic machinery of the proteasome. Given that inhibiting the proteasome is a common therapeutic strategy in multiple myeloma (MM), we investigated Rpn10 and found that it is highly expressed in MM cells, compared to PBMCs, and its expression is inversely correlated with overall survival and positively correlated with disease progression in MM patients. Inducible knockout or knockdown of Rpn10 decreased MM cell viability both in vitro and in vivo by triggering the accumulation of polyubiquitinated proteins, MM cell cycle arrest, and MM cell death through caspase-dependent- and unfolded-protein-response-related apoptosis. Proteomic analysis revealed that inhibiting Rpn10 in MM increased autophagy, antigen presentation and the activation of CD4+ T cells and NK cells. We then developed an in vitro AlphaScreen binding assay for high-throughput screening and identified a novel Rpn10 inhibitor, SB699551. Treating MM cell lines, leukemic cell lines, and primary MM patient cells with SB699551 significantly decreased cell viability without affecting the viability of normal PBMCs. SB699551 inhibited the proliferation of MM cells even in the presence of microenvironmental cells and without blocking the catalytic activity of the 20S proteasome unit or the deubiquitinating activity of the 19S unit. Rpn10 blockade by SB699551 triggered MM cell death via similar pathways as the genetic strategy. Xenograft animal models found that SB699551 was well-tolerated, inhibited tumor growth, and prolonged survival. Our data suggests that inhibiting Rpn10 will enhance cytotoxicity and overcome proteasome-inhibitor resistance in MM, providing the basis for further optimization studies of Rpn10 inhibitors for clinical application.