The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition

Giada Bianchi, Laura Oliva, Paolo Cascio, Niccolò Pengo, Francesca Fontana, Fulvia Cerruti, Andrea Orsi, Elena Pasqualetto, Alexandre Mezghrani, Valeria Calbi, Giovanni Palladini, Nicola Giuliani, Kenneth C. Anderson, Roberto Sitia, Simone Cenci

Research output: Contribution to journalArticle

Abstract

Proteasome inhibitors(PIs) are effective against multiple myeloma(MM), but the mechanisms of action and bases of individual susceptibility remain unclear. Recent work linked PI sensitivity to protein synthesis and proteasome activity, raising the question whether different levels of proteasome expression and workload underlie PI sensitivity in MM cells(MMCs). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMCs express lower proteasome levels and higher proteaso- mal workload than relatively PI-resistant MMCs, resulting in the accumulation of polyubiquitinated proteins at the expense of free ubiquitin(proteasome stress). Manipulating proteasome expression or workload alters apoptotic sensitivity to PI, demonstrating a cause-effect relationship between proteasome stress and apo-ptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmarkneoplastic plasma cells, in positive correlation with immuno-globulin(Ig) content, both intra- and inter-patient. Moreover, overall proteasome activity of primary MMCs inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degra-dative capacity represents a critical determinant of apoptotic sensitivity of MMCs to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.

Original languageEnglish
Pages (from-to)3040-3049
Number of pages10
JournalBlood
Volume113
Issue number13
DOIs
Publication statusPublished - Mar 26 2009

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology

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    Bianchi, G., Oliva, L., Cascio, P., Pengo, N., Fontana, F., Cerruti, F., Orsi, A., Pasqualetto, E., Mezghrani, A., Calbi, V., Palladini, G., Giuliani, N., Anderson, K. C., Sitia, R., & Cenci, S. (2009). The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition. Blood, 113(13), 3040-3049. https://doi.org/10.1182/blood-2008-08-172734