Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure

• Proteasome inhibitor Bortezomib, at its low-nanomolar IC50, achieves unexpectedly severe proteasome inhibition within cells.
• Bortezomib achieves this severe inhibition of intracellular proteasomes by triggering changes in proteasome structure.
• The greatest inhibition is observed in multiple myeloma cells, myeloma being one of the few cancers which Bortezomib can treat.

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.