Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.
Immunomodulatory drugs (IMiDs), such as thalidomide and its derivatives lenalidomide and pomalidomide, are key treatment modalities for hematologic malignancies, particularly multiple myeloma (MM) and del(5q) myelodysplastic syndrome (MDS). Cereblon (CRBN), a substrate receptor of the CRL4 ubiquitin ligase complex, is the primary target by which IMiDs mediate anticancer and teratogenic effects. Here we identify a ubiquitin-independent physiological chaperone-like function of CRBN that promotes maturation of the basigin (BSG; also known as CD147) and solute carrier family 16 member 1 (SLC16A1; also known as MCT1) proteins. This process allows for the formation and activation of the CD147-MCT1 transmembrane complex, which promotes various biological functions, including angiogenesis, proliferation, invasion and lactate export. We found that IMiDs outcompete CRBN for binding to CD147 and MCT1, leading to destabilization of the CD147-MCT1 complex. Accordingly, IMiD-sensitive MM cells lose CD147 and MCT1 expression after being exposed to IMiDs, whereas IMiD-resistant cells retain their expression. Furthermore, del(5q) MDS cells have elevated CD147 expression, which is attenuated after IMiD treatment. Finally, we show that BSG (CD147) knockdown phenocopies the teratogenic effects of thalidomide exposure in zebrafish. These findings provide a common mechanistic framework to explain both the teratogenic and pleiotropic antitumor effects of IMiDs.
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Ruth
R
Eichner
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Michael
M
Heider
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Vanesa
V
Fernández-Sáiz
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
Frauke
F
van Bebber
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Anne-Kathrin
AK
Garz
Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.
Simone
S
Lemeer
Institute of Pathology, Universität Würzburg, Würzburg, Germany.|Comprehensive Cancer Center Mainfranken, Universität Würzburg, Würzburg, Germany.
Martina
M
Rudelius
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Bianca-Sabrina
BS
Targosz
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Laura
L
Jacobs
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Anna-Maria
AM
Knorn
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
Jolanta
J
Slawska
Medizinische Klinik und Poliklinik I, Universitätsklinikum Carl-Gustav-Carus, Technische Universität, Dresden, Germany.
Uwe
U
Platzbecker
Department of Hematology, Oncology and Clinical Immunology, Heinrich-Heine-University, Düsseldorf, Germany.
Ulrich
U
Germing
Department of Internal Medicine III, University of Ulm, Ulm, Germany.
Christian
C
Langer
Division of Hematology and Medical Oncology, Department of Internal Medicine II, Würzburg University Medical Center, Würzburg, Germany.
Stefan
S
Knop
Division of Hematology and Medical Oncology, Department of Internal Medicine II, Würzburg University Medical Center, Würzburg, Germany.
Herrmann
H
Einsele
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Christian
C
Peschel
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.|Biomedical Center, Ludwig-Maximilians University Munich, Munich, Germany.
Christian
C
Haass
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Ulrich
U
Keller
German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.|Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
Bettina
B
Schmid
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Katharina S
KS
Götze
German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.|Department of Proteomics and Bioanalytics, Technische Universität München, Freising, Germany.|Center for Integrated Protein Science Munich (CIPSM), Freising, Germany.
Bernhard
B
Kuster
Department of Medicine III, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.|German Cancer Consortium (DKTK), Heidelberg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
Florian
F
Bassermann
D048868:Adaptor Proteins, Signal Transducing; D051926:Basigin / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D018797:Cell Cycle Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D006801:Humans; D007155:Immunologic Factors / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D000077269:Lenalidomide; D009101:Multiple Myeloma / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D009190:Myelodysplastic Syndromes / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D015513:Oncogene Proteins / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D010447:Peptide Hydrolases / Q000187:drug effects* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000187:drug effects* / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000187:drug effects; D064793:Teratogenesis / Q000187:drug effects* / Q000235:genetics; D013792:Thalidomide / Q000031:analogs & derivatives / Q000494:pharmacology*; D044767:Ubiquitin-Protein Ligases
D048868:Adaptor Proteins, Signal Transducing; C497886:BSG protein, human; C502543:CRBN protein, human; D018797:Cell Cycle Proteins; D007155:Immunologic Factors; D007166:Immunosuppressive Agents; C115081:MCTS1 protein, human; D015513:Oncogene Proteins; D012333:RNA, Messenger; D051926:Basigin; D013792:Thalidomide; C467566:pomalidomide; D044767:Ubiquitin-Protein Ligases; D010447:Peptide Hydrolases; D000077269:Lenalidomide