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Blood, 26 March 2009, Vol. 113, No. 13, pp. 3040-3049.
Prepublished online as a Blood First Edition Paper on January 22, 2009; DOI 10.1182/blood-2008-08-172734.
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Submitted August 7, 2008
Accepted December 31, 2008
The proteasome load vs. capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition
Giada Bianchi, Laura Oliva, Paolo Cascio, Niccolo Pengo, Francesca Fontana, Fulvia Cerruti, Andrea Orsi, Elena Pasqualetto, Alexandre Mezghrani, Valeria Calbi, Giovanni Palladini, Nicola Giuliani, Kenneth C. Anderson, Roberto Sitia, and Simone Cenci*
Division of Genetics and Cell Biology, DiBiT, San Raffaele Scientific Institute, Milano, Italy
Department of Veterinary Morphophysiology, University of Torino, Torino, Italy
Universita Vita-Salute San Raffaele, Milano, Italy
Myeloma Unit, San Raffaele Scientific Institute, Milano, Italy
Institut de Genomique Fonctionelle, CNRS, Montpellier, France
Hematology and BMT Unit, San Raffaele Scientific Institute, Milano, Italy
Amyloidosis Center, Biotechnology Research Laboratories, Fondazione IRCCS Policlinico San Matteo, Department of Biochemistry, University of Pavia, Pavia, Italy
Hematology and BMT Center, University of Parma, Parma, Italy
The LeBow Institute for Myeloma Therapeutics and Jerome Lipper Center for Myeloma Research, Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, United States
BoNetwork, San Raffaele Scientific Institute, Milano, Italy
* Corresponding author; email: cenci.simone{at}hsr.it.
Proteasome inhibitors (PI) 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 (MMC). Exploiting human MM lines characterized by differential PI sensitivity, we report that highly sensitive MMC express lower proteasome levels and higher proteasomal workload than relatively PI-resistant MMC, resulting in the accumulation of poly-ubiquitinated 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 apoptotic responses in MMC. Intracellular immunostaining in primary, patient-derived MMC reveals that poly-ubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with Ig content, both intra- and inter-patient. Moreover, overall proteasome activity of primary MMC inversely correlates with apoptotic sensitivity to PI. Altogether, our data indicate that the balance between proteasome workload and degradative capacity represents a critical determinant of apoptotic sensitivity of MMC to PI, potentially providing a framework for identifying indicators of responsiveness and designing novel combination therapies.
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