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PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis
Pyroptosis is critical for macrophages against pathogen infection, but its role and mechanism in cancer cells remain unclear. PD-L1 has been detected in the nucleus with unknown function. Here, we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumor necro...
Autores principales: | , , , , , , , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653546/ https://www.ncbi.nlm.nih.gov/pubmed/32929201 http://dx.doi.org/10.1038/s41556-020-0575-z |
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author | Hou, Junwei Zhao, Rongce Xia, Weiya Chang, Chiung-Wen You, Yun Hsu, Jung-Mao Nie, Lei Chen, Yeh Wang, Yu-Chuan Liu, Chunxiao Wang, Wei-Jan Wu, Yun Ke, Baozhen Hsu, Jennifer L. Huang, Kebin Ye, Zu Yang, Yi Xia, Xianghou Li, Yintao Li, Chia-Wei Shao, Bin Tainer, John A. Hung, Mien-Chie |
author_facet | Hou, Junwei Zhao, Rongce Xia, Weiya Chang, Chiung-Wen You, Yun Hsu, Jung-Mao Nie, Lei Chen, Yeh Wang, Yu-Chuan Liu, Chunxiao Wang, Wei-Jan Wu, Yun Ke, Baozhen Hsu, Jennifer L. Huang, Kebin Ye, Zu Yang, Yi Xia, Xianghou Li, Yintao Li, Chia-Wei Shao, Bin Tainer, John A. Hung, Mien-Chie |
author_sort | Hou, Junwei |
collection | PubMed |
description | Pyroptosis is critical for macrophages against pathogen infection, but its role and mechanism in cancer cells remain unclear. PD-L1 has been detected in the nucleus with unknown function. Here, we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumor necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing gasdermin C (GSDMC) gene transcription. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8, and GSDMC are required for macrophage-derived TNFα-induced tumor necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/Caspas-8 mediates non-canonical pyroptosis pathway in cancer cells, causing tumor necrosis. |
format | Online Article Text |
id | pubmed-7653546 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
record_format | MEDLINE/PubMed |
spelling | pubmed-76535462021-03-14 PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis Hou, Junwei Zhao, Rongce Xia, Weiya Chang, Chiung-Wen You, Yun Hsu, Jung-Mao Nie, Lei Chen, Yeh Wang, Yu-Chuan Liu, Chunxiao Wang, Wei-Jan Wu, Yun Ke, Baozhen Hsu, Jennifer L. Huang, Kebin Ye, Zu Yang, Yi Xia, Xianghou Li, Yintao Li, Chia-Wei Shao, Bin Tainer, John A. Hung, Mien-Chie Nat Cell Biol Article Pyroptosis is critical for macrophages against pathogen infection, but its role and mechanism in cancer cells remain unclear. PD-L1 has been detected in the nucleus with unknown function. Here, we show that PD-L1 switches TNFα-induced apoptosis to pyroptosis in cancer cells, resulting in tumor necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing gasdermin C (GSDMC) gene transcription. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8, and GSDMC are required for macrophage-derived TNFα-induced tumor necrosis in vivo. Moreover, high expression of GSDMC correlates with poor survival. Antibiotic chemotherapy drugs induce pyroptosis in breast cancer. These findings identify a non-immune checkpoint function of PD-L1 and provide an unexpected concept that GSDMC/Caspas-8 mediates non-canonical pyroptosis pathway in cancer cells, causing tumor necrosis. 2020-09-14 2020-10 /pmc/articles/PMC7653546/ /pubmed/32929201 http://dx.doi.org/10.1038/s41556-020-0575-z Text en Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:http://www.nature.com/authors/editorial_policies/license.html#terms |
spellingShingle | Article Hou, Junwei Zhao, Rongce Xia, Weiya Chang, Chiung-Wen You, Yun Hsu, Jung-Mao Nie, Lei Chen, Yeh Wang, Yu-Chuan Liu, Chunxiao Wang, Wei-Jan Wu, Yun Ke, Baozhen Hsu, Jennifer L. Huang, Kebin Ye, Zu Yang, Yi Xia, Xianghou Li, Yintao Li, Chia-Wei Shao, Bin Tainer, John A. Hung, Mien-Chie PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title | PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title_full | PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title_fullStr | PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title_full_unstemmed | PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title_short | PD-L1-Mediated Gasdermin C Expression Switches Apoptosis to Pyroptosis in Cancer Cells and Facilitates Tumor Necrosis |
title_sort | pd-l1-mediated gasdermin c expression switches apoptosis to pyroptosis in cancer cells and facilitates tumor necrosis |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7653546/ https://www.ncbi.nlm.nih.gov/pubmed/32929201 http://dx.doi.org/10.1038/s41556-020-0575-z |
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