Modulation of cereblon levels by anti-myeloma agents

Abstract

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.

Keywords::

• Cancer
• CRBN
• IMIDs
• myeloma
• thalidomide

Acknowledgements

The authors wish to thank members of the Pandiella laboratory for discussion and encouragement. E.D-R. and work in our laboratory are supported by the Spanish Association for Cancer Research (AECC). This work was partially supported by grants from the Ministry of Economy and Competitiveness of Spain (BFU2009-07728/BMC and BFU2012-39151) and Instituto de Salud Carlos III (RD06/0020/0041 and RD/0036/0003). Our Cancer Research Institute, and the work carried out at our laboratory receive support from the European Community through the regional development funding program (FEDER), and from the Fundación Ramón Areces.

Potential conflict of interest

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Supplementary material available online

Supplementary Figure 1.