BMB Reports

  • 제59권3호
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  • Pages.193-200
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  • 2026
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  • 1976-6696(pISSN)
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  • 1976-670X(eISSN)
생화학분자생물학회 (Korean Society for Biochemistry and Molecular Biology)
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Cereblon upregulation overcomes thalidomide resistance in multiple myeloma through mitochondrial functional reprogramming

  • Jubert Marquez (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Nammi Park (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Jae Hyeog Choi (New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation) ;
  • Maria Victoria Faith Garcia (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Jessa Flores (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Bayalagmaa Nyamaa (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Jung Eun Seol (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Hyoung Kyu Kim (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University) ;
  • Myung Geun Shin (Department of Laboratory Medicine, Chonnam National University Medical School) ;
  • Sae Gwang Park (Laboratory for Medical Oncology, Department of Microbiology and Immunology, College of Medicine, Inje University) ;
  • Jin Han (Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University)
  • 투고 : 2024.08.14
  • 심사 : 2025.01.03
  • 발행 : 2026.03.31
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초록

Patients with multiple myeloma develop resistance to thalidomide during therapy, and the mechanisms to counteract thalidomide resistance remain elusive. Here, we explored the interaction between cereblon and mitochondrial function to mitigate thalidomide resistance in multiple myeloma. Measurements of cell viability, ATP production, mitochondrial membrane potential, mitochondrial ROS, and protein expression via western blotting were conducted in vitro using KSM20 and KMS26 cells to assess the impact of thalidomide on multiple myeloma. An in vivo analysis using xenografted multiple myeloma cells in BALB/c nude mice revealed that KMS20 cells were resistant to thalidomide, whereas KMS26 cells were sensitive. Overexpression of CRBN in a KMS20 xenograft model reversed its resistance to thalidomide, reduced tumor growth, and significantly extended the survival rate of the mice. Overexpression of CRBN in thalidomide-resistant KMS20 cells during thalidomide treatment led to effective cell death through the modulation of mitochondrial function and protein expression, mediated by AMPKα1 signaling. Conversely, both genetic and pharmacological knockdowns of CRBN rendered KMS26 cells resistant to thalidomide, indicating that CRBN level modulation directly influences mitochondrial functions. These findings propose that targeting cereblon offers a promising strategy in overcoming thalidomide resistance in multiple myeloma through mitochondrial reprogramming.

키워드

과제정보

This work was supported by the Basic Research Laboratory program and Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Korean government (RS-2023-00243640, RS-2023-00270463, RS-2023-00221673, NRF-2022R1I1A1A01072399, RS-2022-NR075454) and by Korea Basic Science Institute (National Research Facilities and Equipment Center) grant funded by the Ministry of Education (2023RIA6C101B008 [RS-2023-NF001312]).

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