Molecular basis of bortezomib resistance: Proteasome subunit 25 (PSMB5) gene mutation and overexpression of PSMB5 protein

Ruud Oerlemans, Niels E. Franke, Yehuda G. Assaraf, Jacqueline Cloos, Ina Van Zantwijk, Celia R. Berkers, George L. Scheffer, Kabir Debipersad, Katharina Vojtekova, Clara Lemos, Joost W. Van Der Heijden, Bauke Ylstra, Godefridus J. Peters, Gertjan L. Kaspers, Ben A.C. Dijkmans, Rik J. Scheper, Gerrit Jansen

Onderzoeksoutput: Bijdrage aan tijdschriftArtikelpeer review

360 Citaten (Scopus)

Samenvatting

The proteasome inhibitor bortezomib is a novel anticancer drug that has shown promise in the treatment of refractory multiple myeloma. However, its clinical efficacy has been hampered by the emergence of drug-resistance phenomena, the molecular basis of which remains elusive. Toward this end, we here developed high levels (45- to 129-fold) of acquired resistance to bortezomib in human myelomonocytic THP1 cells by exposure to stepwise increasing (2.5-200 nM) concentrations of bortezomib. Study of the molecular mechanism of bortezomib resistance in these cells revealed (1) an Ala49Thr mutation residing in a highly conserved bortezomib-binding pocket in the proteasome β5-subunit (PSMB5) protein, (2) a dramatic overexpression (up to 60-fold) of PSMB5 protein but not of other proteasome subunits including PSMB6, PSMB7, and PSMA7, (3) high levels of cross-resistance to β5 subunit-targeted cytotoxic peptides 4A6, MG132, MG262, and ALLN, but not to a broad spectrum of chemotherapeutic drugs, (4) no marked changes in chymotrypsin-like proteasome activity, and (5) restoration of bortezomib sensitivity in bortezomib-resistant cells by siRNA-mediated silencing of PSMB5 gene expression. Collectively, these findings establish a novel mechanism of bortezomib resistance associated with the selective overexpression of a mutant PSMB5 protein.

Originele taal-2Engels
Pagina's (van-tot)2489-2499
Aantal pagina's11
TijdschriftBlood
Volume112
Nummer van het tijdschrift6
DOI's
StatusGepubliceerd - 15 sep. 2008
Extern gepubliceerdJa

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