Abstract:
:Multiple myeloma is a B-cell malignancy for which no curative therapies exist to date, despite enormous research efforts. The remarkable activity of the proteasome inhibitor bortezomib (PS-341, Velcade) observed in clinical trials of patients with relapsed refractory myeloma has led to investigations of the role of the ubiquitin-proteasome pathway in the pathogenesis of myeloma. Here we report a biochemical analysis of proteasome activity and composition in myeloma cells exposed to PS-341 in the presence or absence of cytokines present in the bone marrow milieu. We observed that the myeloma cell lines MM1.S, RPMI8226, and U266 contain active immunoproteasomes, the amount of which is enhanced by IFN-gamma and tumor necrosis factor-alpha. Using a radiolabeled active site-directed probe specific for proteasome catalytic subunits, we show that PS-341 targets the beta5 and beta1 subunits in a concentration-dependent manner. Furthermore, PS-341 also targeted the corresponding catalytic subunits of the immunoproteasome, beta5i and beta1i, respectively. These data suggest that PS-341 targets both normal and immunoproteasome species to a similar extent in myeloma cells.
journal_name
Cancer Resjournal_title
Cancer researchauthors
Altun M,Galardy PJ,Shringarpure R,Hideshima T,LeBlanc R,Anderson KC,Ploegh HL,Kessler BMdoi
10.1158/0008-5472.CAN-05-0506subject
Has Abstractpub_date
2005-09-01 00:00:00pages
7896-901issue
17eissn
0008-5472issn
1538-7445pii
65/17/7896journal_volume
65pub_type
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