Modulation of cereblon levels by anti-myeloma agents

• Published in: Leukemia & lymphoma Vol. 57; no. 1; pp. 167 - 176
• Main Authors: Díaz-Rodríguez, Elena, Pandiella, Atanasio
• Format: Journal Article
• Language: English
• Published: United States Taylor & Francis 02.01.2016
• Subjects: Antineoplastic Agents - pharmacology; Apoptosis - drug effects; Apoptosis - genetics; Cancer; Cell Cycle - drug effects; Cell Cycle - genetics; Cell Line, Tumor; Cell Proliferation; CRBN; Cytosol - metabolism; DNA-Binding Proteins - metabolism; Gene Expression Regulation, Neoplastic - drug effects; Humans; IMIDs; Multiple Myeloma - genetics; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Multiprotein Complexes - metabolism; myeloma; Peptide Hydrolases - genetics; Peptide Hydrolases - metabolism; Protein Binding; thalidomide; Thalidomide - analogs & derivatives; Thalidomide - pharmacology; myeloma; CRBN; thalidomide; IMIDs; Cancer
• ISSN: 1042-8194; 1029-2403
• DOI: 10.3109/10428194.2015.1037752

The use of thalidomide derivatives (IMIDs) has improved multiple myeloma prognosis, through an unknown mechanism of action. Recently one molecular target, the cereblon (CRBN) protein, has been identified. CRBN acts by binding to DDB1-CUL4-ROC1 forming a ubiquitin ligase multiprotein complex. We have generated antibodies to different regions of CRBN protein, and analyzed the biological consequences of augmenting or decreasing CRBN levels. CRBN was expressed in all the myeloma cell lines tested, independently of their sensitivity to IMIDs, and the CRBN-DDB1-CUL4 complex was efficiently formed. At the molecular level, long-term treatment with IMIDs induced a slight decrease in CRBN levels and a reduction in the CRBN-DDB1-CUL4 complex. Interestingly, treatment with other anti-myeloma drugs downregulated cellular contents of CRBN, and in a much faster fashion. These results suggest that CRBN is an important mediator of the cellular response to IMIDs, but also critical in the maintenance of cell viability and/or proliferation.