ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer
Abstract Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptos...
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| Language: | English |
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BMC
2023-10-01
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| Series: | Journal of Experimental & Clinical Cancer Research |
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| Online Access: | https://doi.org/10.1186/s13046-023-02834-7 |
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| author | Pingping Su Xiaodan Mao Jincheng Ma Lixiang Huang Lirui Yu Shuting Tang Mingzhi Zhuang Zhonglei Lu Kelvin Stefan Osafo Yuan Ren Xinrui Wang Xite Lin Leyi Huang Xiaoli Huang Elena Ioana Braicu Jalid Sehouli Pengming Sun |
| author_facet | Pingping Su Xiaodan Mao Jincheng Ma Lixiang Huang Lirui Yu Shuting Tang Mingzhi Zhuang Zhonglei Lu Kelvin Stefan Osafo Yuan Ren Xinrui Wang Xite Lin Leyi Huang Xiaoli Huang Elena Ioana Braicu Jalid Sehouli Pengming Sun |
| author_sort | Pingping Su |
| collection | DOAJ |
| description | Abstract Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. Results Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells. |
| format | Article |
| id | doaj-art-9ca48bb33a7045c4bcf82fe273e82f40 |
| institution | Kabale University |
| issn | 1756-9966 |
| language | English |
| publishDate | 2023-10-01 |
| publisher | BMC |
| record_format | Article |
| series | Journal of Experimental & Clinical Cancer Research |
| spelling | doaj-art-9ca48bb33a7045c4bcf82fe273e82f402025-01-26T12:57:51ZengBMCJournal of Experimental & Clinical Cancer Research1756-99662023-10-0142112210.1186/s13046-023-02834-7ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancerPingping Su0Xiaodan Mao1Jincheng Ma2Lixiang Huang3Lirui Yu4Shuting Tang5Mingzhi Zhuang6Zhonglei Lu7Kelvin Stefan Osafo8Yuan Ren9Xinrui Wang10Xite Lin11Leyi Huang12Xiaoli Huang13Elena Ioana Braicu14Jalid Sehouli15Pengming Sun16Laboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityCollege of Biological Science and Engineering, Fuzhou UniversityCollege of Biological Science and Engineering, Fuzhou UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityMedical Research Center, College of Clinical Medicine for Obstetrics and Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityDepartment of Obstetrics and Gynecology, The First Affiliated Hospital, Fujian Medical UniversityDepartment of Gynecology and Obstetrics, Charité Virchow University HospitalDepartment of Gynecology and Obstetrics, Charité Virchow University HospitalLaboratory of Gynecologic Oncology, Department of Gynecology, College of Clinical Medicine for Obstetrics & Gynecology and Pediatrics, Fujian Maternity and Child Health Hospital, Fujian Medical UniversityAbstract Background Tumor cells can resist chemotherapy-induced pyroptosis through glycolytic reprogramming. Estrogen-related receptor alpha (ERRα) is a central regulator of cellular energy metabolism associated with poor cancer prognosis. Herein, we refine the oncogenic role of ERRα in the pyroptosis pathway and glycolytic metabolism. Methods The interaction between ERRα and HIF-1α was verified using co-immunoprecipitation. The transcriptional binding sites of ERRα and NLRP3 were confirmed using dual-luciferase reporter assay and cleavage under targets and tagmentation (CUT&Tag). Flow cytometry, transmission electron microscopy, scanning electron microscopy, cell mito stress test, and extracellular acidification rate analysis were performed to investigate the effects of ERRα on the pyroptosis pathway and glycolytic metabolism. The results of these experiments were further confirmed in endometrial cancer (EC)-derived organoids and nude mice. In addition, the expression of ERRα-related pyroptosis genes was analyzed using The Cancer Genome Atlas and Gene Expression Omnibus database. Results Triggered by a hypoxic microenvironment, highly expressed ERRα could bind to the promoter of NLRP3 and inhibit caspase-1/GSDMD signaling, which reduced inflammasome activation and increased pyroptosis resistance, thereby resulting in the resistance of cancer cells to cisplatin. Moreover, ERRα activated glycolytic rate-limiting enzyme to bridge glycolytic metabolism and pyroptosis in EC. This phenomenon was further confirmed in EC-derived organoids and nude mice. CUT & Tag sequencing and The Cancer Genome Atlas database analysis showed that ERRα participated in glycolysis and programmed cell death, which resulted in EC progression. Conclusions ERRα inhibits pyroptosis in an NLRP3-dependent manner and induces glycolytic metabolism, resulting in cisplatin resistance in EC cells.https://doi.org/10.1186/s13046-023-02834-7Endometrial cancerPyroptosisMetabolic reprogrammingERRαCisplatin resistance |
| spellingShingle | Pingping Su Xiaodan Mao Jincheng Ma Lixiang Huang Lirui Yu Shuting Tang Mingzhi Zhuang Zhonglei Lu Kelvin Stefan Osafo Yuan Ren Xinrui Wang Xite Lin Leyi Huang Xiaoli Huang Elena Ioana Braicu Jalid Sehouli Pengming Sun ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer Journal of Experimental & Clinical Cancer Research Endometrial cancer Pyroptosis Metabolic reprogramming ERRα Cisplatin resistance |
| title | ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer |
| title_full | ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer |
| title_fullStr | ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer |
| title_full_unstemmed | ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer |
| title_short | ERRα promotes glycolytic metabolism and targets the NLRP3/caspase-1/GSDMD pathway to regulate pyroptosis in endometrial cancer |
| title_sort | errα promotes glycolytic metabolism and targets the nlrp3 caspase 1 gsdmd pathway to regulate pyroptosis in endometrial cancer |
| topic | Endometrial cancer Pyroptosis Metabolic reprogramming ERRα Cisplatin resistance |
| url | https://doi.org/10.1186/s13046-023-02834-7 |
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