Academic Journal
The role of chaperone-mediated autophagy in bortezomib resistant multiple myeloma
| العنوان: | The role of chaperone-mediated autophagy in bortezomib resistant multiple myeloma |
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| المؤلفون: | Nikesitch, N, Rebeiro, P, Ho, LL, Pothula, S, Wang, XM, Khong, T, Quek, H, Spencer, A, Lee, CS, Roberts, TL, Ling, SCW |
| المصدر: | urn:ISSN:2073-4409 ; Cells, 10, 12, 3464 |
| بيانات النشر: | MDPI |
| سنة النشر: | 2021 |
| المجموعة: | UNSW Sydney (The University of New South Wales): UNSWorks |
| مصطلحات موضوعية: | 3101 Biochemistry and Cell Biology, 32 Biomedical and Clinical Sciences, 3211 Oncology and Carcinogenesis, 31 Biological Sciences, Orphan Drug, Stem Cell Research, Rare Diseases, Hematology, Cancer, 2.1 Biological and endogenous factors, 5.1 Pharmaceuticals, Aged, Apoptosis, Bortezomib, Cell Line, Tumor, Cell Proliferation, Chaperone-Mediated Autophagy, Drug Resistance, Neoplasm, Female, Flow Cytometry, Gene Expression Regulation, Neoplastic, Humans, Lysosomal-Associated Membrane Protein 2, Male, Middle Aged, Multiple Myeloma, Proteolysis |
| الوصف: | Background: Multiple myeloma (MM) remains incurable despite high-dose chemotherapy, autologous stem cell transplants and novel agents. Even with the improved survival of MM patients treated with novel agents, including bortezomib (Bz), the therapeutic options in relapsed/refractory MM remain limited. The majority of MM patients eventually develop resistance to Bz, although the mechanisms of the resistance are poorly understood. Methods: Lysosomal associated membrane protein 2A (LAMP2A) mRNA and protein expression levels were assessed in ex vivo patient samples and a Bz-resistant MM cell line model by in real-rime PCR, western blotting and immunohistochemistry. In vitro modelling of chaperone-mediated autophagy (CMA) activity in response to ER stress were assessed by western blotting and confocal microscopy. The effects of CMA inhibition on MM cell via-bility and Bz sensitivity in MM cells were assessed by Annexin V/7AAD apoptosis assays using flow cytometry. Results: In this study, there is evidence that CMA, a chaperone-mediated protein degradation pathway, is upregulated in Bz-resistant MM and the inhibition of CMA sensitises resistant cells to Bz. The protein levels of LAMP2A, the rate-limiting factor of the CMA pathway, are significantly increased in MM patients resistant to Bz and within our Bz-resistant cell line model. Bz-resistant cell lines also possessed higher basal CMA activity than the Bz-sensitive parent cell line. In MM cell lines, CMA activity was upregulated in response to ER stress induced by Bz. The inhibition of CMA sensi-tises Bz-resistant cells to Bz and the combination of CMA inhibition and Bz in vitro had a more cyto-toxic effect on myeloma cells than Bz alone. Conclusion: In summary, the upregulation of CMA is a potential mechanism of resistance to Bz and a novel target to overcome Bz-resistant MM. |
| نوع الوثيقة: | article in journal/newspaper |
| وصف الملف: | application/pdf |
| اللغة: | unknown |
| Relation: | http://hdl.handle.net/1959.4/103015; https://doi.org/10.3390/cells10123464 |
| DOI: | 10.3390/cells10123464 |
| الاتاحة: | http://hdl.handle.net/1959.4/103015 https://unsworks.unsw.edu.au/bitstreams/6b11aa25-c940-453f-92ac-27fbe4967606/download https://doi.org/10.3390/cells10123464 |
| Rights: | open access ; https://purl.org/coar/access_right/c_abf2 ; CC BY ; https://creativecommons.org/licenses/by/4.0/ ; free_to_read |
| رقم الانضمام: | edsbas.F9F72A83 |
| قاعدة البيانات: | BASE |
| DOI: | 10.3390/cells10123464 |
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