Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells.

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 Res

journal_title

Cancer research

authors

Altun M,Galardy PJ,Shringarpure R,Hideshima T,LeBlanc R,Anderson KC,Ploegh HL,Kessler BM

doi

10.1158/0008-5472.CAN-05-0506

subject

Has Abstract

pub_date

2005-09-01 00:00:00

pages

7896-901

issue

17

eissn

0008-5472

issn

1538-7445

pii

65/17/7896

journal_volume

65

pub_type

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