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

Mikael Altun, Paul J. Galardy, Reshma Shringarpure, Teru Hideshima, Richard LeBlanc, Kenneth C. Anderson, Hidde L. Ploegh, Benedikt M. Kessler

Research output: Contribution to journalArticle

104 Citations (Scopus)

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-γ and tumor necrosis factor-α. Using a radiolabeled active site-directed probe specific for proteasome catalytic subunits, we show that PS-341 targets the β5 and β1 subunits in a concentration-dependent manner. Furthermore, PS-341 also targeted the corresponding catalytic subunits of the immunoproteasome, β5i and β1i, respectively. These data suggest that PS-341 targets both normal and immunoproteasome species to a similar extent in myeloma cells.

Original languageEnglish (US)
Pages (from-to)7896-7901
Number of pages6
JournalCancer Research
Volume65
Issue number17
DOIs
StatePublished - Sep 1 2005
Externally publishedYes

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Proteasome Endopeptidase Complex
Multiple Myeloma
Catalytic Domain
Proteasome Inhibitors
Ubiquitin
Bortezomib
B-Lymphocytes
Tumor Necrosis Factor-alpha
Bone Marrow
Clinical Trials
Cytokines
Cell Line
Research
Neoplasms

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Altun, M., Galardy, P. J., Shringarpure, R., Hideshima, T., LeBlanc, R., Anderson, K. C., ... Kessler, B. M. (2005). Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Research, 65(17), 7896-7901. https://doi.org/10.1158/0008-5472.CAN-05-0506

Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. / Altun, Mikael; Galardy, Paul J.; Shringarpure, Reshma; Hideshima, Teru; LeBlanc, Richard; Anderson, Kenneth C.; Ploegh, Hidde L.; Kessler, Benedikt M.

In: Cancer Research, Vol. 65, No. 17, 01.09.2005, p. 7896-7901.

Research output: Contribution to journalArticle

Altun, M, Galardy, PJ, Shringarpure, R, Hideshima, T, LeBlanc, R, Anderson, KC, Ploegh, HL & Kessler, BM 2005, 'Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells', Cancer Research, vol. 65, no. 17, pp. 7896-7901. https://doi.org/10.1158/0008-5472.CAN-05-0506
Altun M, Galardy PJ, Shringarpure R, Hideshima T, LeBlanc R, Anderson KC et al. Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. Cancer Research. 2005 Sep 1;65(17):7896-7901. https://doi.org/10.1158/0008-5472.CAN-05-0506
Altun, Mikael ; Galardy, Paul J. ; Shringarpure, Reshma ; Hideshima, Teru ; LeBlanc, Richard ; Anderson, Kenneth C. ; Ploegh, Hidde L. ; Kessler, Benedikt M. / Effects of PS-341 on the activity and composition of proteasomes in multiple myeloma cells. In: Cancer Research. 2005 ; Vol. 65, No. 17. pp. 7896-7901.
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