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Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma

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Abstract

Recent studies have suggested the potency of berberine (BBR) for multiple cancer treatments, including multiple myeloma (MM). However, the direct target and underlying mechanism of BBR remain largely understood in MM. Here, we demonstrated that BBR inhibited cell proliferation and acted synergistically with bortezomib in MM.1S cells. BBR treatment induced MM cell cycle arrest by downregulating several cell cycle-related proteins. Murine double minute 2 (MDM2) as a BBR-binding protein was identified by surface plasmon resonance image (SPRi) analysis and molecular docking. Overexpression of MDM2 is associated with MM progression and a poor prognosis. Knockdown MDM2 by siRNA transfection can repress MM malignant progression and attenuate the BBR sensitivity to MM.1S cells. BBR treatment induced the degradation of MDM2 through the ubiquitin–proteasome system and reactivated P53/P21 in MM cells. Overall, our data has illustrated that MDM2, as a binding protein of BBR for the first time, may serve as a potential therapeutic option for MM.

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Abbreviations

BBR:

Berberine

MM:

Multiple myeloma

MGUS:

Monoclonal gammopathy of undetermined significance

SMM:

Smoldering multiple myeloma

MDM2:

Murine double minute 2

MDM4:

Murine double minute 4

IL-6:

Interleukin-6

SPR:

Surface plasmon resonance

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Acknowledgements

This work was supported by grants from the National Natural Science Foundation of China (no. 81170496), Research Project for Practice Development of National TCM Clinical Research Bases (NO. JDZX2015119), The State Key Laboratory of Natural and Biomimetic Drugs (No. K202113) Science and Technology Program of Guangdong Province (No. 2017B 030303001), and Science and Technology Program of Guangzhou City (No. 201604020140, 202206010063). We gratefully acknowledge Guangzhou BetterWays Biotechnology and Guangzhou Fitgene Biotechnology for their assistance in molecular docking and mass spectrum. We thank the Institute of Laboratory Animal Science, School of Medicine, and School of Traditional Chines Medicine at Jinan University for equipment and technical support.

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  1. Chuting Li, Rui Su and Xiuyuan Wang contributed equally to this work.

Authors and Affiliations

  1. Department of Biochemistry and Molecular Biology, Medical College of Jinan University, Guangzhou, 510632, China

    Chuting Li, Ru Su, Xiuyuan Wang, Guiping Huang, Yanjun Liu, Juhua Yang, Zhao Yin, Chunming Gu & Jia Fei

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  1. Chuting Li
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  2. Ru Su
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  3. Xiuyuan Wang
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  7. Zhao Yin
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  8. Chunming Gu
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Contributions

JF conceived of and designed the experiments. CL and RS performed the experiments. XW, YL, JY, GH, and CG analyzed the data. ZY and CL contributed reagents, materials, and analytical tools. JF, CL, and CG wrote the paper.

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Correspondence to Chunming Gu or Jia Fei.

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Li, C., Su, R., Wang, X. et al. Discovery of the oncogenic MDM2, a direct binding target of berberine and a potential therapeutic, in multiple myeloma. Funct Integr Genomics 22, 1031–1041 (2022). https://doi.org/10.1007/s10142-022-00880-6

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