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Molecular basis of bortezomib resistance: proteasome subunit β5 ( PSMB5 ) gene mutation and overexpression of PSMB5 protein

Blood, ISSN: 0006-4971, Vol: 112, Issue: 6, Page: 2489-2499
2008
  • 372
    Citations
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    Usage
  • 250
    Captures
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Metric Options:   Counts1 Year3 Year

Metrics Details

  • Citations
    372
  • Captures
    250

Article Description

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.

Bibliographic Details

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

American Society of Hematology

Biochemistry, Genetics and Molecular Biology; Immunology and Microbiology; Medicine

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