Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells
Abstract Background Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition co...
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| Format: | Article |
| Language: | English |
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BMC
2020-05-01
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| Series: | Cell Communication and Signaling |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s12964-020-00576-z |
| _version_ | 1818047101193420800 |
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| author | Yupei Liang Yanyu Jiang Xing Jin Ping Chen Yongqing Heng Lili Cai Wenjuan Zhang Lihui Li Lijun Jia |
| author_facet | Yupei Liang Yanyu Jiang Xing Jin Ping Chen Yongqing Heng Lili Cai Wenjuan Zhang Lihui Li Lijun Jia |
| author_sort | Yupei Liang |
| collection | DOAJ |
| description | Abstract Background Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. Methods The expression of relevant proteins of NF-κB/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. Results For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate IκBα to block NF-κB activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. Conclusions In our study, we elucidates a novel mechanism of NF-κB/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924). Video abstract Graphical abstract |
| first_indexed | 2024-12-10T10:00:26Z |
| format | Article |
| id | doaj.art-e023111dbf124f6ea887c04d54001848 |
| institution | Directory Open Access Journal |
| issn | 1478-811X |
| language | English |
| last_indexed | 2024-12-10T10:00:26Z |
| publishDate | 2020-05-01 |
| publisher | BMC |
| record_format | Article |
| series | Cell Communication and Signaling |
| spelling | doaj.art-e023111dbf124f6ea887c04d540018482022-12-22T01:53:22ZengBMCCell Communication and Signaling1478-811X2020-05-0118111110.1186/s12964-020-00576-zNeddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cellsYupei Liang0Yanyu Jiang1Xing Jin2Ping Chen3Yongqing Heng4Lili Cai5Wenjuan Zhang6Lihui Li7Lijun Jia8Cancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineSchool of Basic Medical Sciences, Zhengzhou UniversityCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineDepartment of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer CenterCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineCancer Institute, Longhua Hospital, Shanghai University of Traditional Chinese MedicineAbstract Background Protein neddylation plays a tumor-promoting role in esophageal cancer. Our previous study demonstrated that neddylation inhibition induced the accumulation of ATF4 to promote apoptosis in esophageal cancer cells. However, it is completely unknown whether neddylation inhibition could induce autophagy in esophageal cancer cells and affect the expression of other members of ATF/CREB subfamily, such as ATF3. Methods The expression of relevant proteins of NF-κB/Catalase/ATF3 pathway after neddylation inhibition was determined by immunoblotting analysis and downregulated by siRNA silencing for mechanistic studies. ROS generation upon MLN4924 treatment was determined by H2-DCFDA staining. The proliferation inhibition induced by MLN4924 was evaluated by ATPLite assay and apoptosis was evaluated by Annexin V /PI double staining. Results For the first time, we reported that MLN4924, a specific inhibitor of Nedd8-activating enzyme, promoted the expression of ATF3 to induce autophagy in esophageal cancer. Mechanistically, MLN4924 inhibited the activity of CRLs and induced the accumulation of its substrate IκBα to block NF-κB activation and Catalase expression. As a result, MLN4924 activated ATF3-induced protective autophagy, thereby inhibiting MLN4924-induced apoptosis, which could be alleviated by ATF3 silencing. Conclusions In our study, we elucidates a novel mechanism of NF-κB/Catalase/ATF3 pathway in MLN4924-induced protective autophagy in esophageal cancer cells, which provides a sound rationale and molecular basis for combinational anti-ESCC therapy with knockdown ATF3 and neddylation inhibitor (e.g. MLN4924). Video abstract Graphical abstracthttp://link.springer.com/article/10.1186/s12964-020-00576-zNeddylationMLN4924NF-κB/catalase/ATF3AutophagyApoptosisEsophageal Cancer |
| spellingShingle | Yupei Liang Yanyu Jiang Xing Jin Ping Chen Yongqing Heng Lili Cai Wenjuan Zhang Lihui Li Lijun Jia Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells Cell Communication and Signaling Neddylation MLN4924 NF-κB/catalase/ATF3 Autophagy Apoptosis Esophageal Cancer |
| title | Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells |
| title_full | Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells |
| title_fullStr | Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells |
| title_full_unstemmed | Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells |
| title_short | Neddylation inhibition activates the protective autophagy through NF-κB-catalase-ATF3 Axis in human esophageal cancer cells |
| title_sort | neddylation inhibition activates the protective autophagy through nf κb catalase atf3 axis in human esophageal cancer cells |
| topic | Neddylation MLN4924 NF-κB/catalase/ATF3 Autophagy Apoptosis Esophageal Cancer |
| url | http://link.springer.com/article/10.1186/s12964-020-00576-z |
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