| Cereblon upregulation overcomes thalidomide resistance in multiple myeloma through mitochondrial functional reprogramming |
Jubert Marquez  1,4,# (Postdoctoral Researcher), Nammi Park1,# (Postdoctoral Researcher), Jae Hyeog Choi2,# (Postdoctoral Researcher), Maria Victoria Faith Garcia1,3 (Postdoctoral Researcher), Jessa Flores1,3 (Ph.D. Student), Bayalagmaa Nyamaa1,5 (Professor), Jung Eun Seol1 (Professor), Hyoung Kyu Kim1,3 (Professor), Myung Geun Shin6 (Professor), Sae Gwang Park7 (Professor), Jin Han 1,* (Professor) |
1Basic Research Laboratory, Department of Physiology, College of Medicine, Smart Marine Therapeutic Center, Cardiovascular and Metabolic Disease Core Research Center, Inje University, Busan, 47392, South Korea,
2New Drug Development Center, Daegu-Gyeongbuk Medical Innovation Foundation, Daegu 41061, Republic of Korea,
3Department of Health Science and Technology, College of Medicine, Inje University, Busan, 47392, Korea,
4Department of Biology, De La Salle University, Manila, 1004, Philippines,
5Department of Hematology, School of Medicine, Mongolian National University of Medical Sciences, Ulaanbaatar, 14210, Mongolia,
6Department of Laboratory Medicine, Chonnam National University Medical School, Gwangju 61469, Republic of Korea,
7Laboratory for Medical Oncology, Department of Microbiology and Immunology, College of Medicine, Inje University, Busan, 47392, Korea |
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Abstract
Multiple myeloma patients develop resistance to thalidomide during therapy, and the mechanism of overcoming thalidomide resistance remains to be uncovered. Here, we investigated the relationship between cereblon and mitochondrial function to overcome thalidomide resistance in multiple myeloma. Cell viability, ATP production, mitochondrial membrane potential, mitochondrial ROS, and protein expression via western blotting were measured in vitro using KSM20 and KMS26 cells to characterize the effectiveness of thalidomide in regulating multiple myeloma. An in vivo analysis using the different multiple myeloma cells xenografted in BALB/c nude mice showed that KMS20 cells were thalidomide-resistant, while KMS26 cells were thalidomide-sensitive. CRBN overexpression in a KMS20 xenograft model reversed its resistance to thalidomide, decreased tumor growth, and significantly prolonged the survival rate of the mice. CRBN overexpression in thalidomide-resistant KMS20 cells during thalidomide treatment effectively killed the cells through the regulation of mitochondrial function and protein expression as mediated by AMPKメ1 signaling. Conversely, genetic and pharmacological knockdown of CRBN rendered KMS26 cells thalidomide resistant, demonstrating that modulation of CRBN level directly regulated mitochondrial functions. These results suggest that targeting cereblon presents a novel perspective in overcoming thalidomide resistance in multiple myeloma through mitochondrial reprogramming.
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| Abstract, Accepted Manuscript [Submitted on August 14, 2024, Accepted on January 3, 2025] |
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