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PARP1 inhibitors induce pyroptosis via caspase 3-mediated gasdermin E cleavage.
Kim, Chiho; Wang, Xu-Dong; Jang, Seoyeon; Yu, Yonghao.
Afiliação
  • Kim C; Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Wang XD; Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA.
  • Jang S; Department of Molecular Biology, University of Texas Southwestern Medical Center, Dallas, TX, 75390, USA.
  • Yu Y; Department of Molecular Pharmacology and Therapeutics, Vagelos College of Physicians and Surgeons, Columbia University Irving Medical Center, New York, NY, 10032, USA. Electronic address: yy3213@cumc.columbia.edu.
Biochem Biophys Res Commun ; 646: 78-85, 2023 02 26.
Article em En | MEDLINE | ID: mdl-36706709
The identification of PARP1 as a therapeutic target for BRCA1/2-deficient cells has led to a paradigm shift for the treatment of human malignancies with BRCA1/2 mutations. However, our understanding of the mechanism of action of PARP1 inhibitors (PARPi) is still evolving. It is being increasingly appreciated that the immunomodulatory function of PARPi is a critical contributor of the anti-tumor effects of these compounds. Here, we identify a novel cell death effector pathway for PARPi where PARPi induces inflammatory pyroptosis that is mediated by caspase 3-dependent cleavage of GSDME. Caspase 3 is activated upon PARPi treatment which directly cleaves GSDME and, subsequently induces pyroptosis. Genetic and pharmacological experiments show that the presence of the PARP1 protein with uncompromised DNA binding capability is required for PARPi-induced pyroptosis, suggesting that PARP1 trapping is a key driver of this phenomenon. Importantly, we show that PARPi-induced GSDME cleavage and pyroptosis occurred only in the BRCA1-deficient cells, but not in those reconstituted with BRCA1 wild-type (WT). These findings suggest that pyroptosis could be a novel aspect of the immunomodulatory function of PARPi. Our studies could also offer new insights to the potential biomarkers and therapeutic strategies to achieve better anti-tumor effects of PARPi for BRCA-deficient tumors with low GSDME expression.
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Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piroptose / Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Assunto principal: Piroptose / Neoplasias Tipo de estudo: Prognostic_studies Limite: Humans Idioma: En Ano de publicação: 2023 Tipo de documento: Article