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Cell and Tumor Biology |
Departments of 1 Cancer Biology, 2 Molecular Pathology, 3 Surgical Oncology, and 4 Gastrointestinal Medical Oncology, University of Texas M.D. Anderson Cancer Center, Houston, Texas and 5 Department of Microbiology and Immunology, Sylvester Cancer Center, University of Miami School of Medicine, Miami, Florida
Requests for reprints: David J. McConkey, Department of Cancer Biology, 173, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030. Phone: 713-792-8591; Fax: 713-792-8747; E-mail: dmcconke{at}mdanderson.org.
Bortezomib (Velcade, formerly known as PS-341) is a boronic acid dipeptide derivative that is a selective and potent inhibitor of the proteasome. We hypothesized that proteasome inhibition would lead to an accumulation of misfolded proteins in the cell resulting in endoplasmic reticulum (ER) stress. The ability of bortezomib to induce ER stress and the unfolded protein response was investigated in a human pancreatic cancer cell line, L3.6pl. Bortezomib increased expression of ER stress markers, CHOP and BiP, but inhibited PKR-like ER kinase and subsequent phosphorylation of eukaryotic initiation factor 2
(eif2), both of which are key events in translational suppression. These effects resulted in an accumulation of ubiquitylated proteins leading to protein aggregation and proteotoxicity. Peptide inhibitor or small interfering RNA targeting ER-resident caspase-4 blocked DNA fragmentation, establishing a central role for caspase-4 in bortezomib-induced cell death. The translation inhibitor cycloheximide abrogated bortezomib-induced protein aggregation, caspase-4 processing, and all other characteristics of apoptosis. Because malignant cells have higher protein synthesis rates than normal cells, they may be more prone to protein aggregation and proteotoxicity and possess increased sensitivity to bortezomib-induced apoptosis. Taken together, the results show that bortezomib induces a unique type of ER stress compared with other ER stress agents characterized by an absence of eif2 phosphorylation, ubiquitylated protein accumulation, and proteotoxicity. (Cancer Res 2005; 65(24): 11510-9)
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