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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.
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NEOPLASIA
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
From the Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL; and the Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL.
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 5 different MM cell lines display similar patterns of sensitivity to 3 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 prosurvival/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 proapoptotic/terminal UPR, including PERK, the ER stress–specific eIF-2 kinase; ATF4, an ER stress–induced transcription factor; and its proapoptotic 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 to function as secretory cells.
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