The DOI matches its Crossref record; 55 of the 55 references it cites were found in a registry or an index.
Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein
Abstract
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.
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Cites
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A Phase 2 Study of Bortezomib in Relapsed, Refractory Myeloma
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Cancer drug resistance: an evolving paradigm
Holohan, C., Van Schaeybroeck, S., Longley, D. B., & Johnston, P. G. (2013) · Nature Reviews Cancer · doi:10.1038/nrc3599 · Cited by 4,681
Proteasome inhibitors in cancer therapy
Manasanch, E. E., & Orlowski, R. Z. (2017) · Nature Reviews Clinical Oncology · doi:10.1038/nrclinonc.2016.206 · Cited by 1,024
Mitochondrial metabolism promotes adaptation to proteotoxic stress
Tsvetkov, P., Detappe, A., Cai, K., Keys, H. R., Brune, Z., Ying, W., Thiru, P., Reidy, M., Kugener, G., Rossen, J., et al. (2019) · Nature Chemical Biology · doi:10.1038/s41589-019-0291-9 · Cited by 645
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Endoplasmic Reticulum Stress in Malignancy
Clarke, H. J., Chambers, J. E., Liniker, E., & Marciniak, S. J. (2014) · Cancer Cell · doi:10.1016/j.ccr.2014.03.015 · Cited by 462
Metadata
- Authors
- Oerlemans, R., Franke, N. E., Assaraf, Y. G., Cloos, J., van Zantwijk, I., Berkers, C. R., Scheffer, G. L., Debipersad, K., Vojtekova, K., Lemos, C., van der Heijden, J. W., Ylstra, B., Peters, G. J., Kaspers, G. L., Dijkmans, B. A. C., Scheper, R. J., & Jansen, G.
- Venue
- Blood
- Publisher
- American Society of Hematology
- Published
- 2008-09-15
- Volume
- 112
- Issue
- 6
- Pages
- 2489-2499
- ISSN
- 0006-4971 (ISSN-L)
- 1528-0020
- OpenAlex
- W2010163650
- Cited by
- 454
- References
- 55
- FWCI
- 7.44
- Type
- journal article
- Language
- en
- Open access
- closed
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- CoChat. (2026). Citation check: Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein. https://app.cochat.ai/papers/10.1182/blood-2007-08-104950
- The paper
- Oerlemans, R., Franke, N. E., Assaraf, Y. G., Cloos, J., van Zantwijk, I., Berkers, C. R., Scheffer, G. L., Debipersad, K., Vojtekova, K., Lemos, C., van der Heijden, J. W., Ylstra, B., Peters, G. J., Kaspers, G. L., Dijkmans, B. A. C., Scheper, R. J., & Jansen, G. (2008). Molecular basis of bortezomib resistance: proteasome subunit β5 (PSMB5) gene mutation and overexpression of PSMB5 protein. Blood. https://doi.org/10.1182/blood-2007-08-104950
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Bibliographic data: Semantic Scholar, OpenAlex, Crossref.
Contains information from the Semantic Scholar Academic Graph Datasets, made available under the ODC Attribution License (ODC-BY 1.0).
Semantic Scholar’s data is described in: Kinney, R., et al. (2023). The Semantic Scholar Open Data Platform. arXiv:2301.10140.
