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Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway

Acta Pharmacologica Sinica volume 44, pages 1464–1474 (2023)Cite this article

Abstract

Proteasomes are overexpressed in multiple myeloma (MM) and proteasomal inhibitors (PIs) have been widely used for the treatment of MM. PIs are reported to induce MM cell apoptosis but impair necroptosis. In the present study, we found that PIs MG132 and bortezomib induce MM cell pyroptosis, a novel type of cell death, in a GSDME-dependent manner. Lack of GSDME totally blocks PI-induced pyroptosis. Interestingly, we found that Caspase-3/6/7/9 are all involved in pyroptosis triggered by PIs because the specific inhibitor of each caspase ablates GSDME activation. PIs markedly reduce mitochondrial membrane potential. Moreover, PIs disrupt the interaction of Bcl-2 and BAX, induce cytochrome c release from mitochondria to cytosol and activate GSDME. Furthermore, we found that overexpression of an N-terminal portion of GSDME suffices to release cytochrome c from mitochondria and to activate Caspase-3/9, suggesting N-GSDME might penetrate the mitochondrial membrane. Consistent with Bcl-2 inhibition, BAX can induce MM cell pyroptosis in a GSDME-dependent manner. In accordance with these findings, inhibition of Bcl-2 synergizes with PIs to induce MM cell pyroptosis. Therefore, the present study indicates that PIs trigger MM cell pyroptosis via the mitochondrial BAX/GSDME pathway and provides a rationale for combined treatment of MM with Bcl-2 and proteasome inhibitors to increase therapeutic efficiency via induction of pyroptosis.

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Fig. 1: PIs induce myeloma cell pyroptosis.
Fig. 2: PIs activate GSDME in association with Caspase-3 but not Caspase-1.
Fig. 3: Inhibition of Caspase-3, -6, -7 and -9 ablates PI-triggered cleavage of GSDME in myeloma cell pyroptosis.
Fig. 4: GSDME is required for myeloma cell pyroptosis induced by inhibition of proteasomes.
Fig. 5: N-terminal GSDME activates Caspase-9/3 by promoting Cyto c release from mitochondria.
Fig. 6: Inhibition of Bcl-2 enhances PI-induced myeloma cell pyroptosis.
Fig. 7: BAX promotes myeloma cell pyroptosis in a GSDME-dependent manner.

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Acknowledgements

The author extended many thanks to Prof. Michael F. Moran, The Hospital for Sick Children, University of Toronto, Toronto, Canada, for his critical reading and editing of the manuscript. This project was partly supported by National Natural Science Foundation of China (#82170176, #81970194), by the National Key Research and Development Program of China (#2022YFC2705003), by Guangzhou Medical University Discipline Construction Funds (Basic Medicine) (#JCXKJS2022A05), by Guangzhou Key Discipline of Medicine (Geriatric Medicine, #ZDXK202103).

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Authors and Affiliations

  1. Guangzhou Institute of Cardiovascular Diseases, Guangdong Key Laboratory of Vascular Diseases, State Key Laboratory of Respiratory Diseases, the Second Affiliated Hospital of Guangzhou Medical University, Guangzhou, 510260, China

    Jing-pei Liang & Xin-liang Mao

  2. Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China

    Jing-pei Liang, Yuan-ming He, Yao-li Cui, Yue-ning Sun & Xin-liang Mao

  3. GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou Medical University, Guangzhou, 511436, China

    Jing-pei Liang & Xin-liang Mao

  4. Department of Orthopaedics, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China

    Gui-song He

  5. Division of Hematology & Oncology, Department of Geriatrics, Guangzhou First People’s Hospital, College of Medicine, South China University of Technology, Guangzhou, 510180, China

    Zhi-gang Zhu

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Contributions

XLM designed the study; JPL, YMH, YLC, and YNS conducted experiments; XLM, JPL, and YMH analyzed data; GSH and ZGZ provided key materials. JPL, YMH and XLM wrote the manuscript.

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Correspondence to Gui-song He, Zhi-gang Zhu or Xin-liang Mao.

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Liang, Jp., He, Ym., Cui, Yl. et al. Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway. Acta Pharmacol Sin 44, 1464–1474 (2023). https://doi.org/10.1038/s41401-023-01060-3

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