ArticleActa pharmacologica Sinica2023
Proteasomal inhibitors induce myeloma cell pyroptosis via the BAX/GSDME pathway.
Article in Acta pharmacologica Sinica, 2023. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 9 papers.
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Who cites it
9 citing papers in PubMed.
- IFI27 and BAX are Essential for GSDME-Mediated Myeloma Cell Pyroptosis.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- p53 Orchestrates the Immunogenic-Tolerogenic Pyroptosis Switch in Non-Small Cell Lung Cancer: A Systems Biology Approach.Computational and structural biotechnology journal · 2026Article
- FOXO3 upregulates and activates GSDME to trigger myeloma cell pyroptosis.International journal of biological sciences · 2026Article
- Bortezomib-loaded hybrid liposome inducing pyroptosis for targeted therapy against colorectal cancer.Drug delivery and translational research · 2025Article
- The multiplex crosstalk between non-coding RNAs, programmed cell death and related mechanisms: a dynamic duo in hematological malignancies.Cancer cell international · 2025Review
- Mitochondrial-dependent apoptosis and STAT3 activation induced by oxidative stress in pemphigus vulgaris.Scientific reports · 2025Article
- Mitochondria: a key regulator of programmed cell death in OP.Frontiers in endocrinology · 2025Review
- Therapeutic strategies of targeting non-apoptotic regulated cell death (RCD) with small-molecule compounds in cancer.Acta pharmaceutica Sinica. B · 2024Review
- Antileukemic effect of venetoclax and hypomethylating agents via caspase-3/GSDME-mediated pyroptosis.Journal of translational medicine · 2023Article
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Authors and funding
7 authors.
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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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