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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. This Article Full Text Full Text (PDF) Supplemental Figures All Versions of this Article: blood-2008-08-172734v1 113/13/3040    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Bianchi, G. Articles by Cenci, S. Search for Related Content PubMed PubMed Citation Articles by Bianchi, G. Articles by Cenci, S. Related Collections Lymphoid Neoplasia Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA The proteasome load versus capacity balance determines apoptotic sensitivity of multiple myeloma cells to proteasome inhibition Giada Bianchi13,*, Laura Oliva1,4,*, Paolo Cascio5, Niccolò Pengo1,2,4, Francesca Fontana1,2,6, Fulvia Cerruti5, Andrea Orsi1,2, Elena Pasqualetto1,4, Alexandre Mezghrani7, Valeria Calbi4,8, Giovanni Palladini9, Nicola Giuliani10, Kenneth C. Anderson3, Roberto Sitia1,2,4,, and Simone Cenci1,2,4,6, 1 Division of Genetics and Cell Biology, San Raffaele Scientific Institute, Milano, Italy; 2 Università Vita-Salute San Raffaele, Milano, Italy; 3 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; 4 Myeloma Unit, San Raffaele Scientific Institute, Milano, Italy; 5 Department of Veterinary Morphophysiology, University of Torino, Torino, Italy; 6 BoNetwork, San Raffaele Scientific Institute, Milano, Italy; 7 Institut de Génomique Fonctionnelle, Centre National de la Recherche Scientifique (CNRS), Montpellier, France; 8 Hematology and Bone Marrow Transplantation (BMT) Unit, San Raffaele Scientific Institute, Milano, Italy; 9 Amyloidosis Center, Biotechnology Research Laboratories, Fondazione Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS) Policlinico San Matteo, Department of Biochemistry, University of Pavia, Pavia, Italy; and 10 Hematology and BMT Center, University of Parma, Parma, Italy 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 proteasomal 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 apoptotic responses in MMCs. Intracellular immunostaining in primary, patient-derived MMCs reveals that polyubiquitinated proteins hallmark neoplastic plasma cells, in positive correlation with immunoglobulin (Ig) content, both intra- and interpatient. 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 degradative 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: J. Kern, G. Untergasser, C. Zenzmaier, B. Sarg, G. Gastl, E. Gunsilius, and M. Steurer GRP-78 secreted by tumor cells blocks the antiangiogenic activity of bortezomib Blood, October 29, 2009; 114(18): 3960 - 3967. [Abstract] [Full Text] [PDF] F. Parlati, S. J. Lee, M. Aujay, E. Suzuki, K. Levitsky, J. B. Lorens, D. R. Micklem, P. Ruurs, C. Sylvain, Y. Lu, et al. Carfilzomib can induce tumor cell death through selective inhibition of the chymotrypsin-like activity of the proteasome Blood, October 15, 2009; 114(16): 3439 - 3447. [Abstract] [Full Text] [PDF] G. Palladini and G. Merlini Current treatment of AL amyloidosis Haematologica, August 1, 2009; 94(8): 1044 - 1048. [Full Text] [PDF]

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