机构：[1]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[2]Department of Liver Surgeryand Liver Transplantation Center, West China Hospital, Sichuan University, Chengdu, China四川大学华西医院[3]Graduate Institute of Biomedical Sciences, Research Centerfor Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan[4]Institute of New Drug Development, China MedicalUniversity, Taichung, Taiwan[5]Department of Biological Science and Technology, China Medical University, Taichung, Taiwan[6]Department of Pathology,The University of Texas MD Anderson Cancer Center, Houston, TX, USA[7]State Key Laboratory for Chemistry and Molecular Engineering of MedicinalResources, School of Chemistry and Pharmacy, Guangxi Normal University, Guilin, China[8]Key Laboratory of Carcinogenesis and Transformation Research(Ministry of Education), Department of Breast Oncology, Peking University Cancer Hospital and Institute, Beijing, China[9]Department of Biotechnology,Asia University, Taichung, Taiwan[10]Department of Liver Surgery, Sun Yat-Sen University Cancer Center, State Key Laboratory of Oncologyin South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
Although pyroptosis is critical for macrophages against pathogen infection, its role and mechanism in cancer cells remains 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 tumour necrosis. Under hypoxia, p-Stat3 physically interacts with PD-L1 and facilitates its nuclear translocation, enhancing the transcription of the gasdermin C (GSDMC) gene. GSDMC is specifically cleaved by caspase-8 with TNFα treatment, generating a GSDMC N-terminal domain that forms pores on the cell membrane and induces pyroptosis. Nuclear PD-L1, caspase-8 and GSDMC are required for macrophage-derived TNFα-induced tumour 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/caspase-8 mediates a non-canonical pyroptosis pathway in cancer cells, causing tumour necrosis.
基金：
National Institutes of Health Cancer Center (Support grant no. P30CA016672) for supporting the High Resolution Electron Microscopy Facility at The University of Texas MD Anderson Cancer Center for the electron microscopy analysis. This work was funded in part by the National Institutes of Health (grant nos P30CA016672 and R01 AI116722 (to M.-C.H.)); a National Breast Cancer Foundation Breast Cancer Research Foundation grant to M.-C.H.; the Patel Memorial Breast Cancer Endowment Fund; the Sister Institution Network Fund for collaboration between The University of Texas MD Anderson Cancer Center and China Medical University (to M.-C.H.); the YingTsai Young Scholar Award (grant no. CMU108-YTY02 to J.-M.H.); China Medical Univesity Start Up Fund (grant no.CMU108-N-02 to W.-J.W.); the NIH (grant nos R35 CA220430 and PO1 CA092584);the Cancer Prevention and Research Institute of Texas (grant no. RP180813); Robert A.Welch Chemistry Chair (to J.A.T.); Cancer Prevention and Research Institute of Texas (grant no. RP160710 to M.-C.H.); and Drug Development Center, Ministry of Education,Taiwan (grant no. 108-2311-B-241-001 to M.-C.H. and Y.C.).
第一作者机构：[1]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
通讯作者：
通讯机构：[1]Department of Molecular and Cellular Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA[3]Graduate Institute of Biomedical Sciences, Research Centerfor Cancer Biology and Center for Molecular Medicine, China Medical University, Taichung, Taiwan[9]Department of Biotechnology,Asia University, Taichung, Taiwan
推荐引用方式(GB/T 7714)：
Junwei Hou,Rongce Zhao,Weiya Xia,et al.PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.[J].NATURE CELL BIOLOGY.2020,22(10):1264-+.doi:10.1038/s41556-020-0575-z.
APA：
Junwei Hou,Rongce Zhao,Weiya Xia,Chiung-Wen Chang,Yun You...&Mien-Chie Hung.(2020).PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis..NATURE CELL BIOLOGY,22,(10)
MLA：
Junwei Hou,et al."PD-L1-mediated gasdermin C expression switches apoptosis to pyroptosis in cancer cells and facilitates tumour necrosis.".NATURE CELL BIOLOGY 22..10(2020):1264-+
生物学