2. Academic Validation
  3. Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway

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

  • Acta Pharmacol Sin. 2023 Feb 20. doi: 10.1038/s41401-023-01060-3.
Jing-Pei Liang 1 2 3,  Yuan-Ming He 2,  Yao-Li Cui 2,  Yue-Ning Sun 2,  Gui-Song He 4,  Zhi-Gang Zhu 5,  Xin-Liang Mao 6 7 8
Affiliations

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.
  • 2 Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China.
  • 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.
  • 4 Department of Orthopaedics, the Second Affiliated Hospital, Guangzhou Medical University, Guangzhou, 510260, China. lhyyhgs@163.com.
  • 5 Division of Hematology & Oncology, Department of Geriatrics, Guangzhou First People's Hospital, College of Medicine, South China University of Technology, Guangzhou, 510180, China. zhuzhigang01@hotmail.com.
  • 6 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. xinliangmao@gzhmu.edu.cn.
  • 7 Guangdong Provincial Key Laboratory of Protein Modification and Degradation, School of Basic Medical Sciences, Guangzhou Medical University, Guangzhou, 511436, China. xinliangmao@gzhmu.edu.cn.
  • 8 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. xinliangmao@gzhmu.edu.cn.
PMID: 36807412 DOI: 10.1038/s41401-023-01060-3
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.

Keywords

BAX; GSDME; mitochondria; multiple myeloma; proteasome.

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