Journal
EBIOMEDICINE
Volume 2, Issue 7, Pages 642-648Publisher
ELSEVIER SCIENCE BV
DOI: 10.1016/j.ebiom.2015.05.016
Keywords
Multiple myeloma; Proteasome; Bortezomib; CTAB-PAGE; Posttranslational modification
Funding
- MRC [MC_PC_13064] Funding Source: UKRI
- Cancer Research UK [15448] Funding Source: researchfish
- Medical Research Council [MC_PC_13064] Funding Source: researchfish
- Medical Research Council [MC_PC_13064] Funding Source: Medline
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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. (C) 2015 The Authors. Published by Elsevier B.V.
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