Du, TingSong, YanRay, ArghyaChauhan, DharminderAnderson, Kenneth2023-02-162018-05-18Du, Ting, Yan Song, Arghya Ray, Dharminder Chauhan, and Kenneth C Anderson. 2021. “Proteomic Analysis Identifies Mechanism(s) of Overcoming Bortezomib Resistance via Targeting Ubiquitin Receptor Rpn13.” Leukemia 35 (2): 550–61.0006-49711528-0020https://nrs.harvard.edu/URN-3:HUL.INSTREPOS:37374384Our 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: (i) increase in superoxide and ROS levels; (ii) activation of caspases, and p53/p21 signaling; (iii) decrease in MCL-1, BCL2, CDC2, cyclin B1 and c-Myc; (iv) ER stress response; and (v) 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.en-USImmunologyCell BiologyBiochemistryHematologyJournal Article2023-02-1610.1182/blood-2019-130236