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
- 372Citations
- 250Captures
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Metrics Details
- Citations372
- Citation Indexes371
- 371
- CrossRef301
- Patent Family Citations1
- Patent Families1
- Captures250
- Readers250
- 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
http://www.sciencedirect.com/science/article/pii/S0006497120598728; http://dx.doi.org/10.1182/blood-2007-08-104950; http://www.scopus.com/inward/record.url?partnerID=HzOxMe3b&scp=53049106912&origin=inward; http://www.ncbi.nlm.nih.gov/pubmed/18565852; https://ashpublications.org/blood/article/112/6/2489/24848/Molecular-basis-of-bortezomib-resistance; https://dx.doi.org/10.1182/blood-2007-08-104950
American Society of Hematology
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