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

Qinqin Xu, Yue xian Hou, Paul R Langlais, Patrick Erickson, James Zhu, Chang Xin Shi, Moulun Luo, Yuanxiao Zhu, Ye Xu, Lawrence J. Mandarino, Alexander Keith Stewart, Xiu-Bao D Chang

Research output: Contribution to journalArticle

17 Citations (Scopus)

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.

Original languageEnglish (US)
Article number297
JournalBMC Cancer
Volume16
Issue number1
DOIs
StatePublished - May 3 2016

Fingerprint

Multiple Myeloma
Cell Survival
Carrier Proteins
Growth
MicroRNAs
Ubiquitin-Protein Ligases
Immunoprecipitation
Histidine
Pharmaceutical Preparations
Cell Death
Western Blotting
Apoptosis
Cell Line
lenalidomide

Keywords

  • Argonaute 2 (AGO2)
  • Cereblon (CRBN)
  • Immunomodulatory drug (IMiD)
  • Lenalidomide
  • MicroRNA (miRNA)
  • Multiple myeloma (MM)

ASJC Scopus subject areas

  • Genetics
  • Oncology
  • Cancer Research

Cite this

Xu, Q., Hou, Y. X., Langlais, P. R., Erickson, P., Zhu, J., Shi, C. X., ... Chang, X-B. D. (2016). Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. BMC Cancer, 16(1), [297]. https://doi.org/10.1186/s12885-016-2331-0

Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. / Xu, Qinqin; Hou, Yue xian; Langlais, Paul R; Erickson, Patrick; Zhu, James; Shi, Chang Xin; Luo, Moulun; Zhu, Yuanxiao; Xu, Ye; Mandarino, Lawrence J.; Stewart, Alexander Keith; Chang, Xiu-Bao D.

In: BMC Cancer, Vol. 16, No. 1, 297, 03.05.2016.

Research output: Contribution to journalArticle

Xu, Q, Hou, YX, Langlais, PR, Erickson, P, Zhu, J, Shi, CX, Luo, M, Zhu, Y, Xu, Y, Mandarino, LJ, Stewart, AK & Chang, X-BD 2016, 'Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival', BMC Cancer, vol. 16, no. 1, 297. https://doi.org/10.1186/s12885-016-2331-0
Xu, Qinqin ; Hou, Yue xian ; Langlais, Paul R ; Erickson, Patrick ; Zhu, James ; Shi, Chang Xin ; Luo, Moulun ; Zhu, Yuanxiao ; Xu, Ye ; Mandarino, Lawrence J. ; Stewart, Alexander Keith ; Chang, Xiu-Bao D. / Expression of the cereblon binding protein argonaute 2 plays an important role for multiple myeloma cell growth and survival. In: BMC Cancer. 2016 ; Vol. 16, No. 1.
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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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AU - Erickson, Patrick

AU - Zhu, James

AU - Shi, Chang Xin

AU - Luo, Moulun

AU - Zhu, Yuanxiao

AU - Xu, Ye

AU - Mandarino, Lawrence J.

AU - Stewart, Alexander Keith

AU - Chang, Xiu-Bao D

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N2 - 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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