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DUT enhances drug resistance to proteasome inhibitors via promoting mitochondrial function in multiple myeloma.
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- معلومة اضافية
- المصدر:
Publisher: Irl Press At Oxford University Press Country of Publication: England NLM ID: 8008055 Publication Model: Print Cited Medium: Internet ISSN: 1460-2180 (Electronic) Linking ISSN: 01433334 NLM ISO Abbreviation: Carcinogenesis Subsets: MEDLINE
- بيانات النشر:
Publication: Oxford : Irl Press At Oxford University Press
Original Publication: [New York, IRL Press]
- الموضوع:
- نبذة مختصرة :
Acquired chemoresistance to proteasome inhibitors (PIs), such as bortezomib (BTZ), becomes an intractable obstacle in the management of multiple myeloma (MM) in the clinic, but the underlying mechanisms are still not well elucidated. In the current study, we established bortezomib-resistant (BR) myeloma cells and performed stable isotope labeling by amino acids in cell culture (SILAC) assay to screen profiled protein expression. The level of deoxyuridine triphosphatase (DUT), an important enzyme of nucleotide metabolism, increased in the BR MM cells. Retrospective analysis indicated patients with higher DUT expression had poorer responses to PI-based treatment and clinical outcomes. DUT knockdown by RNAi effectively minimized BTZ resistance in MM cells. Moreover, DUT knockdown was accompanied with the downregulation of proliferating cell nuclear antigen (PCNA), contributing to decelerating cell growth, as well as augmented apoptosis due to bortezomib treatment. In contrast, DUT overexpression in parental MM.1S and LP-1 cells enhanced BTZ resistance. Furthermore, acquired resistance to BTZ could trigger the modulation of mitochondrial metabolism and function, as evidenced by elevated expression of genes associated with mitochondrial metabolism, as well as altered oxygen consumption rate and adenosine triphosphate (ATP) production in BR MM cells. DUT inhibition partially attenuated mitochondrial modulation, and instead favored an early impairment of mitochondrial integrity upon BTZ exposure so as to restrict MM progression and overcome drug resistance to BTZ treatment both in vitro and in vivo. In conclusion, we unveiled previously unrecognized effects of DUT on acquired drug resistance of MM, thus manipulating DUT may be efficacious for sensitizing MM cells to PIs.
(© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)
- الرقم المعرف:
0 (Antineoplastic Agents)
69G8BD63PP (Bortezomib)
1173-82-6 (deoxyuridine triphosphate)
0 (PCNA protein, human)
EC 3.4.25.1 (Proteasome Endopeptidase Complex)
0 (Proteasome Inhibitors)
- الموضوع:
Date Created: 20221125 Date Completed: 20230214 Latest Revision: 20230214
- الموضوع:
20240628
- الرقم المعرف:
10.1093/carcin/bgac071
- الرقم المعرف:
36426924
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