GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis
Abstract Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Springer
2024-01-01
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| Series: | Discover Oncology |
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| Online Access: | https://doi.org/10.1007/s12672-024-00860-1 |
| _version_ | 1797355660442075136 |
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| author | Qianwei Zhao Mengdan Yu Jinxia Li Yaoyu Guo Zexuan Wang Kefei Hu Fang Xu Yixian Liu Lili Li Didi Wan Ying Zhao Jian Shang Jintao Zhang |
| author_facet | Qianwei Zhao Mengdan Yu Jinxia Li Yaoyu Guo Zexuan Wang Kefei Hu Fang Xu Yixian Liu Lili Li Didi Wan Ying Zhao Jian Shang Jintao Zhang |
| author_sort | Qianwei Zhao |
| collection | DOAJ |
| description | Abstract Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment. |
| first_indexed | 2024-03-08T14:15:20Z |
| format | Article |
| id | doaj.art-946d33c145f54dd48822c8ebd36883d1 |
| institution | Directory Open Access Journal |
| issn | 2730-6011 |
| language | English |
| last_indexed | 2024-03-08T14:15:20Z |
| publishDate | 2024-01-01 |
| publisher | Springer |
| record_format | Article |
| series | Discover Oncology |
| spelling | doaj.art-946d33c145f54dd48822c8ebd36883d12024-01-14T12:27:48ZengSpringerDiscover Oncology2730-60112024-01-0115111710.1007/s12672-024-00860-1GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosisQianwei Zhao0Mengdan Yu1Jinxia Li2Yaoyu Guo3Zexuan Wang4Kefei Hu5Fang Xu6Yixian Liu7Lili Li8Didi Wan9Ying Zhao10Jian Shang11Jintao Zhang12Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityHenan Institute of Medical and Pharmaceutical Sciences, Zhengzhou UniversityAbstract Glutamate dehydrogenase 1 (GLUD1) is an important enzyme in glutamine metabolism. Previously, we found GLUD1 was down-regulated in tumor tissues of hepatocellular carcinoma (HCC) patients by proteomics study. To explore its role in the progression of HCC, the expressional level of GLUD1 was firstly examined and presented as that both the protein and mRNA levels were down-regulated in tumor tissues compared to the normal liver tissues. GLUD1 overexpression significantly inhibited HCC cells proliferation, migration, invasion and tumor growth both in vitro and in vivo, while GLUD1 knocking-down promoted HCC progression. Metabolomics study of GLUD1 overexpressing and control HCC cells showed that 129 differentially expressed metabolites were identified, which mainly included amino acids, bases, and phospholipids. Moreover, metabolites in mitochondrial oxidative phosphorylation system (OXPHOS) were differentially expressed in GLUD1 overexpressing cells. Mechanistic studies showed that GLUD1 overexpression enhanced mitochondrial respiration activity and reactive oxygen species (ROS) production. Excessive ROS lead to mitochondrial apoptosis that was characterized by increased expression levels of p53, Cytochrome C, Bax, Caspase 3 and decreased expression level of Bcl-2. Furthermore, we found that the p38/JNK MAPK pathway was activated in GLUD1 overexpressing cells. N-acetylcysteine (NAC) treatment eliminated cellular ROS and blocked p38/JNK MAPK pathway activation, as well as cell apoptosis induced by GLUD1 overexpression. Taken together, our findings suggest that GLUD1 inhibits HCC progression through regulating cellular metabolism and oxidative stress state, and provide that ROS generation and p38/JNK MAPK pathway activation as promising methods for HCC treatment.https://doi.org/10.1007/s12672-024-00860-1GLUD1MetabolismROSp38/JNK MAPK pathwayApoptosis |
| spellingShingle | Qianwei Zhao Mengdan Yu Jinxia Li Yaoyu Guo Zexuan Wang Kefei Hu Fang Xu Yixian Liu Lili Li Didi Wan Ying Zhao Jian Shang Jintao Zhang GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis Discover Oncology GLUD1 Metabolism ROS p38/JNK MAPK pathway Apoptosis |
| title | GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis |
| title_full | GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis |
| title_fullStr | GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis |
| title_full_unstemmed | GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis |
| title_short | GLUD1 inhibits hepatocellular carcinoma progression via ROS-mediated p38/JNK MAPK pathway activation and mitochondrial apoptosis |
| title_sort | glud1 inhibits hepatocellular carcinoma progression via ros mediated p38 jnk mapk pathway activation and mitochondrial apoptosis |
| topic | GLUD1 Metabolism ROS p38/JNK MAPK pathway Apoptosis |
| url | https://doi.org/10.1007/s12672-024-00860-1 |
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