Bortezomib Amplifies Effect on Intracellular Proteasomes by Changing Proteasome Structure.
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 IC(50) - 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.
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
David S
DS
Pitcher
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
Kate
K
de Mattos-Shipley
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
Konstantinos
K
Tzortzis
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
Holger W
HW
Auner
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
Anastasios
A
Karadimitris
Centre for Haematology, Division of Experimental Medicine, Faculty of Medicine, Imperial College London, Hammersmith Campus, Commonwealth Building 4th Floor, Du Cane Road, London W12 0NN, United Kingdom.
Maurits F
MF
Kleijnen
D000069286:Bortezomib / Q000494:pharmacology*; D020134:Catalytic Domain; D045744:Cell Line, Tumor; D006801:Humans; D042541:Intracellular Space / Q000201:enzymology*; D009101:Multiple Myeloma / Q000473:pathology; D046988:Proteasome Endopeptidase Complex / Q000737:chemistry* / Q000378:metabolism*
D000069286:Bortezomib; D046988:Proteasome Endopeptidase Complex
Bortezomib; CTAB-PAGE; Multiple myeloma; Posttranslational modification; Proteasome