Journal Article

DZNE-2020-04970

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Immunomodulatory drugs disrupt the cereblon-CD147-MCT1 axis to exert antitumor activity and teratogenicity.

Eichner, R. ; Heider, M. ; Fernández-Sáiz, V. ; van Bebber, F.DZNE* ; Garz, A.-K. ; Lemeer, S. ; Rudelius, M. ; Targosz, B.-S. ; Jacobs, L. ; Knorn, A.-M. ; Slawska, J. ; Platzbecker, U. ; Germing, U. ; Langer, C. ; Knop, S. ; Einsele, H. ; Peschel, C. ; Haass, C.DZNE* ; Keller, U. ; Schmid, B.DZNE* ; Götze, K. S. ; Kuster, B. ; Bassermann, F. (Corresponding author)

2016
Nature America Inc. New York, NY

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Please use a persistent id in citations: doi:10.1038/nm.4128

Abstract: 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.

Keyword(s): Adaptor Proteins, Signal Transducing (MeSH) ; Basigin: drug effects (MeSH) ; Basigin: genetics (MeSH) ; Basigin: metabolism (MeSH) ; Cell Cycle Proteins: drug effects (MeSH) ; Cell Cycle Proteins: genetics (MeSH) ; Cell Cycle Proteins: metabolism (MeSH) ; Humans (MeSH) ; Immunologic Factors: pharmacology (MeSH) ; Immunosuppressive Agents: pharmacology (MeSH) ; Lenalidomide (MeSH) ; Multiple Myeloma: drug therapy (MeSH) ; Multiple Myeloma: genetics (MeSH) ; Multiple Myeloma: metabolism (MeSH) ; Myelodysplastic Syndromes: drug therapy (MeSH) ; Myelodysplastic Syndromes: genetics (MeSH) ; Myelodysplastic Syndromes: metabolism (MeSH) ; Oncogene Proteins: drug effects (MeSH) ; Oncogene Proteins: genetics (MeSH) ; Oncogene Proteins: metabolism (MeSH) ; Peptide Hydrolases: drug effects (MeSH) ; Peptide Hydrolases: genetics (MeSH) ; Peptide Hydrolases: metabolism (MeSH) ; RNA, Messenger: drug effects (MeSH) ; RNA, Messenger: metabolism (MeSH) ; Reverse Transcriptase Polymerase Chain Reaction (MeSH) ; Signal Transduction: drug effects (MeSH) ; Teratogenesis: drug effects (MeSH) ; Teratogenesis: genetics (MeSH) ; Thalidomide: analogs & derivatives (MeSH) ; Thalidomide: pharmacology (MeSH) ; Ubiquitin-Protein Ligases (MeSH) ; BSG protein, human ; CRBN protein, human ; Cell Cycle Proteins ; Immunologic Factors ; Immunosuppressive Agents ; MCTS1 protein, human ; Oncogene Proteins ; RNA, Messenger ; Basigin ; Thalidomide ; pomalidomide ; Peptide Hydrolases ; Lenalidomide

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Contributing Institute(s):

1. Fish Core Unit (AG Schmid)
2. Molecular Neurodegeneration (AG Haass)

Research Program(s):

1. 342 - Disease Mechanisms and Model Systems (POF3-342) (POF3-342)

Appears in the scientific report 2016

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Database coverage:
; BIOSIS Previews ; Clarivate Analytics Master Journal List ; Current Contents - Clinical Medicine ; Current Contents - Life Sciences ; Ebsco Academic Search ; IF >= 30 ; JCR ; NCBI Molecular Biology Database ; Nationallizenz ; SCOPUS ; Science Citation Index ; Science Citation Index Expanded ; Web of Science Core Collection

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