Autor: |
Marino S; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN. SMarino@uams.edu., Petrusca DN; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Bishop RT; Department of Tumor Biology, H. Lee Moffitt Cancer Research Center and Institute, Tampa, FL., Anderson JL; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Sabol HM; Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR., Ashby C; Department of Biomedical Informatics, University of Arkansas for Medical Sciences, Little Rock, AR., Layer JH; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Cesarano A; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Davé UP; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Perna F; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN., Delgado-Calle J; Department of Physiology and Cell Biology, University of Arkansas for Medical Sciences, Little Rock, AR, USA; Winthrop P. Rockefeller Cancer Institute, University of Arkansas for Medical Sciences, Little Rock, AR., Chirgwin JM; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN, USA; Research Service, Roudebush Veterans Administration Medical Center, Indianapolis, IN., Roodman GD; Department of Medicine, Division of Hematology/Oncology, Indiana University School of Medicine, Indianapolis IN, USA; Research Service, Roudebush Veterans Administration Medical Center, Indianapolis, IN. |
Abstrakt: |
Multiple myeloma (MM) is a malignancy of plasma cells whose antibody secretion creates proteotoxic stress relieved by the N-end rule pathway, a proteolytic system that degrades N-arginylated proteins in the proteasome. When the proteasome is inhibited, protein cargo is alternatively targeted for autophagic degradation by binding to the ZZ-domain of p62/ sequestosome-1. Here, we demonstrate that XRK3F2, a selective ligand for the ZZ-domain, dramatically improved two major responses to the proteasome inhibitor bortezomib (Btz) by increasing: i) killing of human MM cells by stimulating both Btz-mediated apoptosis and necroptosis, a process regulated by p62; and ii) preservation of bone mass by stimulating osteoblast differentiation and inhibiting osteoclastic bone destruction. Co-administration of Btz and XRK3F2 inhibited both branches of the bimodal N-end rule pathway exhibited synergistic anti-MM effects on MM cell lines and CD138+ cells from MM patients, and prevented stromal-mediated MM cell survival. In mice with established human MM, co-administration of Btz and XRK3F2 decreased tumor burden and prevented the progression of MM-induced osteolytic disease by inducing new bone formation more effectively than either single agent alone. The results suggest that p62-ZZ ligands enhance the anti- MM efficacy of proteasome inhibitors and can reduce MM morbidity and mortality by improving bone health. |