TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance
Abstract The E3 ligase TNF receptor-associated factor 4 (TRAF4) is upregulated and closely associated with tumorigenesis and the progression of multiple human malignancies. However, its effect on radiosensitivity in colorectal cancer (CRC) has not been elucidated. The present study found that TRAF4...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Publishing Group
2023-02-01
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| Series: | Cell Death and Disease |
| Online Access: | https://doi.org/10.1038/s41419-023-05637-y |
| _version_ | 1828034976561496064 |
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| author | Xin Dong Xiaoying Li Yu Gan Jie Ding Baojun Wei Li Zhou Wei Cui Wei Li |
| author_facet | Xin Dong Xiaoying Li Yu Gan Jie Ding Baojun Wei Li Zhou Wei Cui Wei Li |
| author_sort | Xin Dong |
| collection | DOAJ |
| description | Abstract The E3 ligase TNF receptor-associated factor 4 (TRAF4) is upregulated and closely associated with tumorigenesis and the progression of multiple human malignancies. However, its effect on radiosensitivity in colorectal cancer (CRC) has not been elucidated. The present study found that TRAF4 was significantly increased in CRC clinical tumor samples. Depletion of TRAF4 impaired the malignant phenotype of CRC cells and sensitized irradiation-induced cell death. Irradiation activated the c-Jun N-terminal kinases (JNKs)/c-Jun signaling via increasing JNKs K63-linked ubiquitination and phosphorylation. Furthermore, c-Jun activation triggered the transcription of the antiapoptotic protein Bcl-xL, thus contributing to the radioresistance of CRC cells. TRAF4 was positively correlated with c-Jun and Bcl-xL, and blocking TRAF4 or inhibiting Bcl-xL with inhibitor markedly promoted ionizing radiation (IR)-induced intrinsic apoptosis and sensitized CRC cells to radiotherapy in vitro and in vivo. Our findings illustrate a potential mechanism of radioresistance, emphasizing the clinical value of targeting the TRAF4/Bcl-xL axis in CRC therapy. |
| first_indexed | 2024-04-10T15:41:04Z |
| format | Article |
| id | doaj.art-82c1e9ca200f499da93da67a797f214e |
| institution | Directory Open Access Journal |
| issn | 2041-4889 |
| language | English |
| last_indexed | 2024-04-10T15:41:04Z |
| publishDate | 2023-02-01 |
| publisher | Nature Publishing Group |
| record_format | Article |
| series | Cell Death and Disease |
| spelling | doaj.art-82c1e9ca200f499da93da67a797f214e2023-02-12T12:24:04ZengNature Publishing GroupCell Death and Disease2041-48892023-02-0114211310.1038/s41419-023-05637-yTRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistanceXin Dong0Xiaoying Li1Yu Gan2Jie Ding3Baojun Wei4Li Zhou5Wei Cui6Wei Li7Department of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityDepartment of Anesthesia, Fuwai Hospital, National Center for Cardiovascular Diseases, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Pathology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital of Central South UniversityDepartment of Clinical Laboratory, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical CollegeDepartment of Radiology, The Third Xiangya Hospital, Central South UniversityAbstract The E3 ligase TNF receptor-associated factor 4 (TRAF4) is upregulated and closely associated with tumorigenesis and the progression of multiple human malignancies. However, its effect on radiosensitivity in colorectal cancer (CRC) has not been elucidated. The present study found that TRAF4 was significantly increased in CRC clinical tumor samples. Depletion of TRAF4 impaired the malignant phenotype of CRC cells and sensitized irradiation-induced cell death. Irradiation activated the c-Jun N-terminal kinases (JNKs)/c-Jun signaling via increasing JNKs K63-linked ubiquitination and phosphorylation. Furthermore, c-Jun activation triggered the transcription of the antiapoptotic protein Bcl-xL, thus contributing to the radioresistance of CRC cells. TRAF4 was positively correlated with c-Jun and Bcl-xL, and blocking TRAF4 or inhibiting Bcl-xL with inhibitor markedly promoted ionizing radiation (IR)-induced intrinsic apoptosis and sensitized CRC cells to radiotherapy in vitro and in vivo. Our findings illustrate a potential mechanism of radioresistance, emphasizing the clinical value of targeting the TRAF4/Bcl-xL axis in CRC therapy.https://doi.org/10.1038/s41419-023-05637-y |
| spellingShingle | Xin Dong Xiaoying Li Yu Gan Jie Ding Baojun Wei Li Zhou Wei Cui Wei Li TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance Cell Death and Disease |
| title | TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance |
| title_full | TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance |
| title_fullStr | TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance |
| title_full_unstemmed | TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance |
| title_short | TRAF4-mediated ubiquitination-dependent activation of JNK/Bcl-xL drives radioresistance |
| title_sort | traf4 mediated ubiquitination dependent activation of jnk bcl xl drives radioresistance |
| url | https://doi.org/10.1038/s41419-023-05637-y |
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