MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions
Objectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metaboli...
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| Format: | Article |
| Language: | English |
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Taylor & Francis Group
2024-12-01
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| Series: | Redox Report |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/13510002.2024.2345455 |
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| author | Hai-Yu Mo Ruo-Bing Wang Meng-Yao Ma Yi Zhang Xin-Yu Li Wang-Rong Wen Yi Han Tian Tian |
| author_facet | Hai-Yu Mo Ruo-Bing Wang Meng-Yao Ma Yi Zhang Xin-Yu Li Wang-Rong Wen Yi Han Tian Tian |
| author_sort | Hai-Yu Mo |
| collection | DOAJ |
| description | Objectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.Methods: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.Results: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.Discussion: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2. |
| format | Article |
| id | doaj-art-885fc61a67754f1fbb20a47ce39e66fa |
| institution | OA Journals |
| issn | 1351-0002 1743-2928 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Redox Report |
| spelling | doaj-art-885fc61a67754f1fbb20a47ce39e66fa2025-08-20T02:37:28ZengTaylor & Francis GroupRedox Report1351-00021743-29282024-12-0129110.1080/13510002.2024.2345455MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditionsHai-Yu Mo0Ruo-Bing Wang1Meng-Yao Ma2Yi Zhang3Xin-Yu Li4Wang-Rong Wen5Yi Han6Tian Tian7Department of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People’s Republic of ChinaDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People’s Republic of ChinaDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People’s Republic of ChinaState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People’s Republic of ChinaClinical Laboratory, The Affiliated Shunde Hospital of Jinan University, Foshan, People’s Republic of ChinaState Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-sen University, Guangzhou, People’s Republic of ChinaDepartment of Medical Biochemistry and Molecular Biology, School of Medicine, Jinan University, Guangzhou, People’s Republic of ChinaObjectives: Cancer cells undergo metabolic reprogramming to adapt to high oxidative stress, but little is known about how metabolic remodeling enables gastric cancer cells to survive stress associated with aberrant reactive oxygen species (ROS) production. Here, we aimed to identify the key metabolic enzymes that protect gastric cancer (GC) cells from oxidative stress.Methods: ROS level was detected by DCFH-DA probes. Multiple cell biological studies were performed to identify the underlying mechanisms. Furthermore, cell-based xenograft and patient-derived xenograft (PDX) model were performed to evaluate the role of MTHFD2 in vivo.Results: We found that overexpression of MTHFD2, but not MTHFD1, is associated with reduced overall and disease-free survival in gastric cancer. In addition, MTHFD2 knockdown reduces the cellular NADPH/NADP+ ratio, colony formation and mitochondrial function, increases cellular ROS and cleaved PARP levels and induces in cell death under hypoxia, a hallmark of solid cancers and a common inducer of oxidative stress. Moreover, genetic or pharmacological inhibition of MTHFD2 reduces tumor burden in both tumor cell lines and patient-derived xenograft-based models.Discussion: our study highlights the crucial role of MTHFD2 in redox regulation and tumor progression, demonstrating the therapeutic potential of targeting MTHFD2.https://www.tandfonline.com/doi/10.1080/13510002.2024.2345455Gastric cancermethylene tetrahydrofolate dehydrogenase 2 (MTHFD2)redox metabolismNADPHreactive oxygen species (ROS) |
| spellingShingle | Hai-Yu Mo Ruo-Bing Wang Meng-Yao Ma Yi Zhang Xin-Yu Li Wang-Rong Wen Yi Han Tian Tian MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions Redox Report Gastric cancer methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) redox metabolism NADPH reactive oxygen species (ROS) |
| title | MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| title_full | MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| title_fullStr | MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| title_full_unstemmed | MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| title_short | MTHFD2-mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| title_sort | mthfd2 mediated redox homeostasis promotes gastric cancer progression under hypoxic conditions |
| topic | Gastric cancer methylene tetrahydrofolate dehydrogenase 2 (MTHFD2) redox metabolism NADPH reactive oxygen species (ROS) |
| url | https://www.tandfonline.com/doi/10.1080/13510002.2024.2345455 |
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