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Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway

Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor...

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Autores principales: Wang, Luoling, Deng, Rilin, Chen, Shuishun, Tian, Renyun, Guo, Mengmeng, Chen, Zihao, Zhang, Yingdan, Li, Huiyi, Liu, Qian, Tang, Songqing, Zhu, Haizhen
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696061/
https://www.ncbi.nlm.nih.gov/pubmed/38049405
http://dx.doi.org/10.1038/s41419-023-06327-5
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author Wang, Luoling
Deng, Rilin
Chen, Shuishun
Tian, Renyun
Guo, Mengmeng
Chen, Zihao
Zhang, Yingdan
Li, Huiyi
Liu, Qian
Tang, Songqing
Zhu, Haizhen
author_facet Wang, Luoling
Deng, Rilin
Chen, Shuishun
Tian, Renyun
Guo, Mengmeng
Chen, Zihao
Zhang, Yingdan
Li, Huiyi
Liu, Qian
Tang, Songqing
Zhu, Haizhen
author_sort Wang, Luoling
collection PubMed
description Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor signalling pathway. In this study, by using morphological observation, fluorescence double staining, LDH release and immunoblot detection, we confirmed for the first time that HGS-ETR1/2 can induce GSDME-mediated pyroptosis in hepatocellular carcinoma cells. Our study found that both inhibition of the AKT signalling pathway and silencing of CPA4 promote pyroptosis, while the overexpression of CPA4 inhibits it. Furthermore, we identified a positive regulatory feedback loop is formed between CPA4 and AKT phosphorylation. Specifically, CPA4 modulates AKT phosphorylation by regulating the expression of the AKT phosphatase PP2A, while inhibition of the AKT signalling pathway leads to a decreased transcription and translation levels of CPA4. Our study reveals a novel mechanism of pyroptosis induced by HGS-ETR1/2, which may provide a crucial foundation for future investigations into cancer immunotherapy.
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spelling pubmed-106960612023-12-06 Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway Wang, Luoling Deng, Rilin Chen, Shuishun Tian, Renyun Guo, Mengmeng Chen, Zihao Zhang, Yingdan Li, Huiyi Liu, Qian Tang, Songqing Zhu, Haizhen Cell Death Dis Article Pyroptosis, a mode of inflammatory cell death, has recently gained significant attention. However, the underlying mechanism remains poorly understood. HGS-ETR1/2 is a humanized monoclonal antibody that can bind to DR4/5 on the cell membrane and induce cell apoptosis by activating the death receptor signalling pathway. In this study, by using morphological observation, fluorescence double staining, LDH release and immunoblot detection, we confirmed for the first time that HGS-ETR1/2 can induce GSDME-mediated pyroptosis in hepatocellular carcinoma cells. Our study found that both inhibition of the AKT signalling pathway and silencing of CPA4 promote pyroptosis, while the overexpression of CPA4 inhibits it. Furthermore, we identified a positive regulatory feedback loop is formed between CPA4 and AKT phosphorylation. Specifically, CPA4 modulates AKT phosphorylation by regulating the expression of the AKT phosphatase PP2A, while inhibition of the AKT signalling pathway leads to a decreased transcription and translation levels of CPA4. Our study reveals a novel mechanism of pyroptosis induced by HGS-ETR1/2, which may provide a crucial foundation for future investigations into cancer immunotherapy. Nature Publishing Group UK 2023-12-04 /pmc/articles/PMC10696061/ /pubmed/38049405 http://dx.doi.org/10.1038/s41419-023-06327-5 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Wang, Luoling
Deng, Rilin
Chen, Shuishun
Tian, Renyun
Guo, Mengmeng
Chen, Zihao
Zhang, Yingdan
Li, Huiyi
Liu, Qian
Tang, Songqing
Zhu, Haizhen
Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title_full Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title_fullStr Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title_full_unstemmed Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title_short Carboxypeptidase A4 negatively regulates HGS-ETR1/2-induced pyroptosis by forming a positive feedback loop with the AKT signalling pathway
title_sort carboxypeptidase a4 negatively regulates hgs-etr1/2-induced pyroptosis by forming a positive feedback loop with the akt signalling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10696061/
https://www.ncbi.nlm.nih.gov/pubmed/38049405
http://dx.doi.org/10.1038/s41419-023-06327-5
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