Pivotal advance: Protein synthesis modulates responsiveness of differentiating and malignant plasma cells to proteasome inhibitors

Simone Cenci, Laura Oliva, Fulvia Cerruti, Enrico Milan, Giada Bianchi, Mary Raule, Alexandre Mezghrani, Elena Pasqualetto, Roberto Sitia, Paolo Cascio

Research output: Contribution to journalArticle

Abstract

A previously unsuspected, considerable proportion of newly synthesized polypeptides are hydrolyzed rapidly by proteasomes, possibly competing with endogenous substrates and altering proteostasis. In view of the anti-cancer effects of PIs, we set out to achieve a quantitative assessment of proteasome workload in cells hallmarked by different PI sensitivity, namely, a panel of MM cells, and in a dynamic model of plasma cell differentiation, a process that confers exquisite PI sensitivity. Our results suggest that protein synthesis is a key determinant of proteasomal proteolytic burden and PI sensitivity. In different MM cells and in differentiating plasma cells, the average proteolytic work accomplished per proteasome ranges over different orders of magnitude, an unexpected degree of variability, with increased workload invariably associated to increased PI sensitivity. The unfavorable load-versus-capacity balance found in highly PI-sensitive MM lines is accounted for by a decreased total number of immunoprotea-somes/cell coupled to enhanced generation of RDPs. Moreover, indicative of cause-effect relationships, attenuating general protein synthesis by the otherwise toxic agent CHX reduces PI sensitivity in activated B and in MM cells. Our data support the view that in plasma cells protein synthesis contributes to determine PI sensitivity by saturating the proteasomal degradative capacity. Quantitating protein synthesis and protea-some workload may thus prove crucial to design novel negative proteostasis regulators against cancer.

Original languageEnglish
Pages (from-to)921-931
Number of pages11
JournalJournal of Leukocyte Biology
Volume92
Issue number5
DOIs
Publication statusPublished - Nov 2012

Keywords

  • Immunoglobulin
  • Plasma cells
  • Proteostasis
  • Proteostenosis

ASJC Scopus subject areas

  • Cell Biology
  • Immunology

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