Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells
Summary: Lenalidomide (LEN) is commonly used as an effective therapeutic agent for multiple myeloma (MM). However, in some patients, primary resistance to LEN is observed, the mechanisms of which remain poorly understood. In this study, we combined a LEN sensitivity assay with proteomics data from 1...
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Elsevier
2024-12-01
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| Series: | iScience |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2589004224026245 |
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| author | Takumi Yamamoto Arisu Furukawa Yue Zhou Nobuaki Kono Shojiro Kitajima Hiroto Ohguchi Yawara Kawano Shingo Ito Norie Araki Sumio Ohtsuki Takeshi Masuda |
| author_facet | Takumi Yamamoto Arisu Furukawa Yue Zhou Nobuaki Kono Shojiro Kitajima Hiroto Ohguchi Yawara Kawano Shingo Ito Norie Araki Sumio Ohtsuki Takeshi Masuda |
| author_sort | Takumi Yamamoto |
| collection | DOAJ |
| description | Summary: Lenalidomide (LEN) is commonly used as an effective therapeutic agent for multiple myeloma (MM). However, in some patients, primary resistance to LEN is observed, the mechanisms of which remain poorly understood. In this study, we combined a LEN sensitivity assay with proteomics data from 15 MM cell lines to identify protein expression profiles associated with primary LEN resistance. Our findings revealed that CSN5 expression is lower in LEN-resistant cell lines than in LEN-sensitive lines. Moreover, we established that CSN5 is degraded via the cullin-RING ubiquitin ligase (CRL)-mediated ubiquitin-proteasome pathway through ubiquitination at lysine 194. Our data suggest that reduced CSN5 expression leads to abnormalities in the ubiquitination cycle of CRL4A, resulting in the inhibition of LEN-mediated degradation of IKZF1 and IKZF3. These findings delineate an additional mechanism of LEN resistance in MM cells and may contribute to the development of alternative therapeutic strategies to overcome LEN resistance. |
| format | Article |
| id | doaj-art-591a78604d6e44db8412ba7e9e8612a2 |
| institution | Kabale University |
| issn | 2589-0042 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Elsevier |
| record_format | Article |
| series | iScience |
| spelling | doaj-art-591a78604d6e44db8412ba7e9e8612a22024-12-22T05:29:13ZengElsevieriScience2589-00422024-12-012712111399Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cellsTakumi Yamamoto0Arisu Furukawa1Yue Zhou2Nobuaki Kono3Shojiro Kitajima4Hiroto Ohguchi5Yawara Kawano6Shingo Ito7Norie Araki8Sumio Ohtsuki9Takeshi Masuda10Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, JapanInstitute for Advanced Biosciences, Keio University, Yamagata 997-0017, JapanInstitute for Advanced Biosciences, Keio University, Yamagata 997-0017, JapanDivision of Disease Epigenetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, JapanDepartment of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanDepartment of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, JapanDepartment of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan; Department of Pharmaceutical Microbiology, Faculty of Life Sciences, Kumamoto University, Kumamoto 862-0973, JapanInstitute for Advanced Biosciences, Keio University, Yamagata 997-0017, Japan; Corresponding authorSummary: Lenalidomide (LEN) is commonly used as an effective therapeutic agent for multiple myeloma (MM). However, in some patients, primary resistance to LEN is observed, the mechanisms of which remain poorly understood. In this study, we combined a LEN sensitivity assay with proteomics data from 15 MM cell lines to identify protein expression profiles associated with primary LEN resistance. Our findings revealed that CSN5 expression is lower in LEN-resistant cell lines than in LEN-sensitive lines. Moreover, we established that CSN5 is degraded via the cullin-RING ubiquitin ligase (CRL)-mediated ubiquitin-proteasome pathway through ubiquitination at lysine 194. Our data suggest that reduced CSN5 expression leads to abnormalities in the ubiquitination cycle of CRL4A, resulting in the inhibition of LEN-mediated degradation of IKZF1 and IKZF3. These findings delineate an additional mechanism of LEN resistance in MM cells and may contribute to the development of alternative therapeutic strategies to overcome LEN resistance.http://www.sciencedirect.com/science/article/pii/S2589004224026245Molecular biologyCell biologyCancerProteomics |
| spellingShingle | Takumi Yamamoto Arisu Furukawa Yue Zhou Nobuaki Kono Shojiro Kitajima Hiroto Ohguchi Yawara Kawano Shingo Ito Norie Araki Sumio Ohtsuki Takeshi Masuda Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells iScience Molecular biology Cell biology Cancer Proteomics |
| title | Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| title_full | Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| title_fullStr | Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| title_full_unstemmed | Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| title_short | Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| title_sort | increased csn5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells |
| topic | Molecular biology Cell biology Cancer Proteomics |
| url | http://www.sciencedirect.com/science/article/pii/S2589004224026245 |
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