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Bortezomib amplifies effect on intracellular proteasomes by changing proteasome structure

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Title: Bortezomib amplifies effect on intracellular proteasomes by changing proteasome structure
Authors: Kleijnen, MF
Item Type: Journal Article
Abstract: © 2015.The proteasome inhibitor Bortezomib is used to treat multiple myeloma (MM). Bortezomib inhibits protein degradation by inactivating proteasomes active-sites. MM cells are exquisitely sensitive to Bortezomib - exhibiting a low-nanomolar IC50 - suggesting that minimal inhibition of degradation suffices to kill MM cells. Instead, we report, a low Bortezomib concentration, contrary to expectation, achieves severe inhibition of proteasome activity in MM cells: the degree of inhibition exceeds what one would expect from the small proportion of active-sites that Bortezomib inhibits. Our data indicate that Bortezomib achieves this severe inhibition by triggering secondary changes in proteasome structure that further inhibit proteasome activity. Comparing MM cells to other, Bortezomib-resistant, cancer cells shows that the degree of proteasome inhibition is the greatest in MM cells and only there leads to proteasome stress, providing an explanation for why Bortezomib is effective against MM but not other cancers.
Issue Date: 28-May-2015
Date of Acceptance: 7-May-2015
URI: http://hdl.handle.net/10044/1/23496
DOI: https://dx.doi.org/10.1016/j.ebiom.2015.05.016
ISSN: 2352-3964
Publisher: Elsevier
Start Page: 642
End Page: 648
Journal / Book Title: EBioMedicine
Volume: 2
Issue: 7
Copyright Statement: © 2015 The Authors. Published by Elsevier B.V. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: Multiple myeloma
Proteasome
Bortezomib
CTAB-PAGE
Posttranslational modification
Publication Status: Published
Appears in Collections:Division of Surgery
Department of Medicine
Faculty of Medicine



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