A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma
Abstract Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2021-05-01
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| Series: | Cell Death Discovery |
| Online Access: | https://doi.org/10.1038/s41420-021-00476-2 |
| _version_ | 1818937966193541120 |
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| author | Ruogu Pan Zhiqing Yuan Yingbin Liu Xuxu Sun Guiyang Wang Xiaopen Wang Junwen Qu Jian Wang Jie Yang Yuzheng Zhao Yi Yang Kewei Li |
| author_facet | Ruogu Pan Zhiqing Yuan Yingbin Liu Xuxu Sun Guiyang Wang Xiaopen Wang Junwen Qu Jian Wang Jie Yang Yuzheng Zhao Yi Yang Kewei Li |
| author_sort | Ruogu Pan |
| collection | DOAJ |
| description | Abstract Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy. |
| first_indexed | 2024-12-20T06:00:21Z |
| format | Article |
| id | doaj.art-969303690b0c4afd8e6678e2b20ab04b |
| institution | Directory Open Access Journal |
| issn | 2058-7716 |
| language | English |
| last_indexed | 2024-12-20T06:00:21Z |
| publishDate | 2021-05-01 |
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| record_format | Article |
| series | Cell Death Discovery |
| spelling | doaj.art-969303690b0c4afd8e6678e2b20ab04b2022-12-21T19:50:56ZengNature Publishing GroupCell Death Discovery2058-77162021-05-017111410.1038/s41420-021-00476-2A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinomaRuogu Pan0Zhiqing Yuan1Yingbin Liu2Xuxu Sun3Guiyang Wang4Xiaopen Wang5Junwen Qu6Jian Wang7Jie Yang8Yuzheng Zhao9Yi Yang10Kewei Li11Department of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory forTumor Microenvironment and Inflammation, Shanghai Jiaotong University School of MedicineDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityDepartment of Biochemistry and Molecular Cell Biology, State Key Laboratory of Oncogenes and Related Genes, Shanghai Key Laboratory forTumor Microenvironment and Inflammation, Shanghai Jiaotong University School of MedicineOptogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and TechnologyOptogenetics & Synthetic Biology Interdisciplinary Research Center, State Key Laboratory of Bioreactor Engineering, Shanghai Collaborative Innovation Center for Biomanufacturing Technology, East China University of Science and TechnologyDepartment of Biliary and Pancreatic Surgery, Renji Hospital, School of Medicine, Shanghai Jiaotong UniversityAbstract Cholangiocarcinoma (CCA) is a type of solid tumor derived from the bile duct epithelium that features universal gemcitabine resistance. Here, we utilized a gene-encoded ROS biosensor probe (HyPer3 probe) to sort subpopulations with different redox statuses from CCA cells. The isolated HyPer-low subpopulation CCA cells, which exhibited relatively lower cellular ROS levels, exhibited higher chemoresistance to gemcitabine than HyPer-high subpopulation CCA cells in vitro and in vivo. Mechanistically, increased expression of MTHFD1 was found in HyPer-low cells. Knocking down MTHFD1 in HyPer-low cells enhanced cellular ROS and restored sensitivity to gemcitabine. Furthermore, the MTHFD1 inhibitor antifolate compound methotrexate (MTX) increased cellular ROS, and combining gemcitabine with MTX effectively suppressed cholangiocarcinoma cell growth. In summary, the MTHFD1 level mediated the heterogeneous cellular redox status in CCA, which resulted in chemoresistance to gemcitabine. Our data suggest a novel strategy for CCA chemotherapy.https://doi.org/10.1038/s41420-021-00476-2 |
| spellingShingle | Ruogu Pan Zhiqing Yuan Yingbin Liu Xuxu Sun Guiyang Wang Xiaopen Wang Junwen Qu Jian Wang Jie Yang Yuzheng Zhao Yi Yang Kewei Li A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma Cell Death Discovery |
| title | A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| title_full | A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| title_fullStr | A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| title_full_unstemmed | A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| title_short | A redox probe screens MTHFD1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| title_sort | redox probe screens mthfd1 as a determinant of gemcitabine chemoresistance in cholangiocarcinoma |
| url | https://doi.org/10.1038/s41420-021-00476-2 |
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