EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein
Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical succes...
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Taylor & Francis Group
2024-12-01
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| Series: | Cancer Biology & Therapy |
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| Online Access: | https://www.tandfonline.com/doi/10.1080/15384047.2024.2402588 |
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| author | Rongqi Guo Yihui Wei Yating Du Luyue Liu Haoqi Zhang Ruiying Ren Ruili Sun Tingting Zhang Xiwen Xiong Lijun Zhao Hongfei Wang Xiaofang Guo Xiaofei Zhu |
| author_facet | Rongqi Guo Yihui Wei Yating Du Luyue Liu Haoqi Zhang Ruiying Ren Ruili Sun Tingting Zhang Xiwen Xiong Lijun Zhao Hongfei Wang Xiaofang Guo Xiaofei Zhu |
| author_sort | Rongqi Guo |
| collection | DOAJ |
| description | Death receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies. |
| format | Article |
| id | doaj-art-007f997d4aac41e2944e64a5883ee62d |
| institution | DOAJ |
| issn | 1538-4047 1555-8576 |
| language | English |
| publishDate | 2024-12-01 |
| publisher | Taylor & Francis Group |
| record_format | Article |
| series | Cancer Biology & Therapy |
| spelling | doaj-art-007f997d4aac41e2944e64a5883ee62d2025-08-20T02:49:47ZengTaylor & Francis GroupCancer Biology & Therapy1538-40471555-85762024-12-0125110.1080/15384047.2024.2402588EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory proteinRongqi Guo0Yihui Wei1Yating Du2Luyue Liu3Haoqi Zhang4Ruiying Ren5Ruili Sun6Tingting Zhang7Xiwen Xiong8Lijun Zhao9Hongfei Wang10Xiaofang Guo11Xiaofei Zhu12Department of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, ChinaHenan Red Cross Blood Center, Xinxiang, ChinaDepartment of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, ChinaDepartments of Laboratory Medicine, Zhoukou Central Hospital, Zhoukou, ChinaDepartment of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaDepartment of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, ChinaHenan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, ChinaDepartment of Microbiology, School of Basic Medical Sciences, Xinxiang Medical University, Xinxiang, ChinaSchool of Forensic Medicine, Xinxiang Medical University, Xinxiang, ChinaHenan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, ChinaHenan Key Laboratory of Immunology and Targeted Drugs, School of Laboratory Medicine, Xinxiang Medical University, Xinxiang, ChinaXinxiang Key Laboratory of Tumor Microenvironment and Immunotherapy, Xinxiang Medical University, Xinxiang, ChinaDepartment of Clinical Laboratory, The Third Affiliated Hospital of Xinxiang Medical University, Xinxiang, ChinaDeath receptor-mediated extrinsic apoptosis system had been developed as a promising therapeutic strategy in clinical oncology, such as TRAIL therapy. However, multiple studies have demonstrated that TRAIL resistance is the biggest problem for disappointing clinical trials despite preclinical success. Targeting cellular FLICE inhibitory protein (cFLIP) is one strategy of combinatorial therapies to overcome resistance to DR-mediated apoptosis due to its negative regulator of extrinsic apoptosis. E × 527 (Selisistat) is a specific inhibitor of SIRT1 activity with safe and well tolerance in clinical trials. Here, we show that E × 527 could strengthen significantly activation of rhFasL-mediated apoptotic signaling pathway and increased apoptotic rate of T leukemia cells with high expression of cFLIP. Mechanically, Inhibition of SIRT1 by E × 527 increased polyubiquitination level of cFLIP via increasing acetylation of Ku70, which could promote proteosomal degradation of cFLIP protein. It implied that combinatorial therapies of E × 527 plus TRAIL may have a potential as a novel clinical application for TRAIL-resistant hematologic malignancies.https://www.tandfonline.com/doi/10.1080/15384047.2024.2402588EX527sirtuins 1T leukemiaapoptosiscellular flice-inhibitory protein |
| spellingShingle | Rongqi Guo Yihui Wei Yating Du Luyue Liu Haoqi Zhang Ruiying Ren Ruili Sun Tingting Zhang Xiwen Xiong Lijun Zhao Hongfei Wang Xiaofang Guo Xiaofei Zhu EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein Cancer Biology & Therapy EX527 sirtuins 1 T leukemia apoptosis cellular flice-inhibitory protein |
| title | EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein |
| title_full | EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein |
| title_fullStr | EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein |
| title_full_unstemmed | EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein |
| title_short | EX527, a sirtuins 1 inhibitor, sensitizes T-cell leukemia to death receptor-mediated apoptosis by downregulating cellular FLICE inhibitory protein |
| title_sort | ex527 a sirtuins 1 inhibitor sensitizes t cell leukemia to death receptor mediated apoptosis by downregulating cellular flice inhibitory protein |
| topic | EX527 sirtuins 1 T leukemia apoptosis cellular flice-inhibitory protein |
| url | https://www.tandfonline.com/doi/10.1080/15384047.2024.2402588 |
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