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BMC Cancer
Published in: BMC Cancer 1/2016

Open Access 01-12-2016 | Research article

Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival

Authors: Qinqin Xu, Yue-xian Hou, Paul Langlais, Patrick Erickson, James Zhu, Chang-Xin Shi, Moulun Luo, Yuanxiao Zhu, Ye Xu, Lawrence J. Mandarino, Keith Stewart, Xiu-bao Chang

Published in: BMC Cancer | Issue 1/2016

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Abstract

Background

Immunomodulatory drugs (IMiDs), such as lenalidomide, are therapeutically active compounds that bind and modulate the E3 ubiquitin ligase substrate recruiter cereblon, thereby affect steady-state levels of cereblon and cereblon binding partners, such as ikaros and aiolos, and induce many cellular responses, including cytotoxicity to multiple myeloma (MM) cells. Nevertheless, it takes many days for MM cells to die after IMiD induced depletion of ikaros and aiolos and thus we searched for other cereblon binding partners that participate in IMiD cytotoxicity.

Methods

Cereblon binding partners were identified from a MM cell line expressing histidine-tagged cereblon by pulling down cereblon and its binding partners and verified by co-immunoprecipitation. IMiD effects were determined by western blot analysis, cell viability assay, microRNA array and apoptosis analysis.

Results

We identified argonaute 2 (AGO2) as a cereblon binding partner and found that the steady-state levels of AGO2 were regulated by cereblon. Upon treatment of IMiD-sensitive MM cells with lenalidomide, the steady-state levels of cereblon were significantly increased, whereas levels of AGO2 were significantly decreased. It has been reported that AGO2 plays a pivotal role in microRNA maturation and function. Interestingly, upon treatment of MM cells with lenalidomide, the steady-state levels of microRNAs were significantly altered. In addition, silencing of AGO2 in MM cells, regardless of sensitivity to IMiDs, significantly decreased the levels of AGO2 and microRNAs and massively induced cell death.

Conclusion

These results support the notion that the cereblon binding partner AGO2 plays an important role in regulating MM cell growth and survival and AGO2 could be considered as a novel drug target for overcoming IMiD resistance in MM cells.
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Metadata
Title
Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival
Authors
Qinqin Xu
Yue-xian Hou
Paul Langlais
Patrick Erickson
James Zhu
Chang-Xin Shi
Moulun Luo
Yuanxiao Zhu
Ye Xu
Lawrence J. Mandarino
Keith Stewart
Xiu-bao Chang
Publication date
01-12-2016
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2016
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-016-2331-0

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