Increased CSN5 expression enhances the sensitivity to lenalidomide in multiple myeloma cells
Takumi Yamamoto,
Arisu Furukawa,
Yue Zhou,
Nobuaki Kono,
Shojiro Kitajima,
Hiroto Ohguchi,
Yawara Kawano,
Shingo Ito,
Norie Araki,
Sumio Ohtsuki,
Takeshi Masuda
Affiliations
Takumi Yamamoto
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
Arisu Furukawa
Department of Pharmaceutical Microbiology, Graduate School of Pharmaceutical Sciences, Kumamoto University, Kumamoto 862-0973, Japan
Yue Zhou
Department of Cancer Cell Biology, Faculty of Pharmaceutical Sciences, University of Toyama, Toyama 930-0194, Japan
Nobuaki Kono
Institute for Advanced Biosciences, Keio University, Yamagata 997-0017, Japan
Shojiro Kitajima
Institute for Advanced Biosciences, Keio University, Yamagata 997-0017, Japan
Hiroto Ohguchi
Division of Disease Epigenetics, Institute of Resource Development and Analysis, Kumamoto University, Kumamoto 860-0811, Japan
Yawara Kawano
Department of Hematology, Rheumatology, and Infectious Disease, Faculty of Life Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Shingo Ito
Department 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, Japan
Norie Araki
Department of Tumor Genetics and Biology, Graduate School of Medical Sciences, Kumamoto University, Kumamoto 860-8556, Japan
Sumio Ohtsuki
Department 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, Japan
Takeshi Masuda
Institute for Advanced Biosciences, Keio University, Yamagata 997-0017, Japan; Corresponding author
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.
