Title |
Immunomodulatory drugs disrupt the cereblon–CD147–MCT1 axis to exert antitumor activity and teratogenicity
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Published in |
Nature Medicine, June 2016
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DOI | 10.1038/nm.4128 |
Pubmed ID | |
Authors |
Ruth Eichner, Michael Heider, Vanesa Fernández-Sáiz, Frauke van Bebber, Anne-Kathrin Garz, Simone Lemeer, Martina Rudelius, Bianca-Sabrina Targosz, Laura Jacobs, Anna-Maria Knorn, Jolanta Slawska, Uwe Platzbecker, Ulrich Germing, Christian Langer, Stefan Knop, Herrmann Einsele, Christian Peschel, Christian Haass, Ulrich Keller, Bettina Schmid, Katharina S Götze, Bernhard Kuster, Florian Bassermann |
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. |
X Demographics
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Country | Count | As % |
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United States | 8 | 22% |
Canada | 1 | 3% |
India | 1 | 3% |
Hungary | 1 | 3% |
Australia | 1 | 3% |
Japan | 1 | 3% |
Ireland | 1 | 3% |
Venezuela, Bolivarian Republic of | 1 | 3% |
New Zealand | 1 | 3% |
Other | 0 | 0% |
Unknown | 21 | 57% |
Demographic breakdown
Type | Count | As % |
---|---|---|
Members of the public | 24 | 65% |
Scientists | 9 | 24% |
Science communicators (journalists, bloggers, editors) | 2 | 5% |
Practitioners (doctors, other healthcare professionals) | 2 | 5% |
Mendeley readers
Geographical breakdown
Country | Count | As % |
---|---|---|
United States | 3 | 1% |
France | 1 | <1% |
Unknown | 215 | 98% |
Demographic breakdown
Readers by professional status | Count | As % |
---|---|---|
Researcher | 47 | 21% |
Student > Ph. D. Student | 38 | 17% |
Student > Master | 20 | 9% |
Student > Bachelor | 17 | 8% |
Other | 13 | 6% |
Other | 32 | 15% |
Unknown | 52 | 24% |
Readers by discipline | Count | As % |
---|---|---|
Biochemistry, Genetics and Molecular Biology | 55 | 25% |
Medicine and Dentistry | 32 | 15% |
Agricultural and Biological Sciences | 22 | 10% |
Pharmacology, Toxicology and Pharmaceutical Science | 16 | 7% |
Chemistry | 13 | 6% |
Other | 21 | 10% |
Unknown | 60 | 27% |