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Blood, 15 June 2006, Vol. 107, No. 12, pp. 4907-4916. Prepublished online as a Blood First Edition Paper on February 28, 2006; DOI 10.1182/blood-2005-08-3531. This Article Full Text (PDF) All Versions of this Article: 2005-08-3531v1 107/12/4907    most recent Alert me when this article is cited Alert me if a correction is posted 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 Obeng, E. A Articles by Boise, L. H Search for Related Content PubMed PubMed Citation Articles by Obeng, E. A Articles by Boise, L. H Social Bookmarking                   What's this?  Previous Article  |  Next Article  Submitted September 1, 2005 Accepted February 13, 2006 Proteasome inhibitors induce a terminal unfolded protein response in multiple myeloma cells Esther A Obeng, Louise M Carlson, Delia M Gutman, William J Harrington, Jr., Kelvin P Lee, and Lawrence H Boise* Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA; Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA * Corresponding author; email: lboise{at}med.miami.edu. Multiple myeloma (MM) is an incurable plasma cell malignancy. The 26S proteasome inhibitor, bortezomib, selectively induces apoptosis in MM cells; however the nature of its selectivity remains unknown. Here we demonstrate that five different MM cell lines display similar patterns of sensitivity to three proteasome inhibitors (PIs), but respond differently to specific NF-B inhibition. We further show that PIs initiate the unfolded protein response (UPR), a signaling pathway activated by the accumulation of misfolded proteins within the endoplasmic reticulum (ER). Consistent with reports that pro-survival/physiologic UPR components are required for B cell differentiation into antibody-secreting cells, we found that MM cells inherently expressed the ER chaperones GRP78/Bip and GRP94/gp96. However, bortezomib rapidly induced components of the pro-apoptotic/terminal UPR including PERK, the ER stress-specific eIF-2 kinase; ATF4, an ER stress-induced transcription factor; and its pro-apoptotic target, CHOP/GADD153. Consistent with our hypothesis that PIs induce the accumulation of misfolded ER-processed proteins, we found that the amount of immunoglobulin subunits retained within MM cells correlated with their sensitivity to PIs. These findings suggest that MM cells have a lower threshold for PI-induced UPR induction and ER stress-induced apoptosis because they constitutively express ER stress survival factors in order to function as secretory cells. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: 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] S. LUST, B. VANHOECKE, M. VAN GELE, J. BOELENS, H. VAN MELCKEBEKE, M. KAILEH, W. VANDEN BERGHE, G. 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