A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer
Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In...
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MDPI AG
2019-11-01
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| Series: | Cancers |
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| Online Access: | https://www.mdpi.com/2072-6694/11/11/1703 |
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| author | Hui-Wen Chiu Ya-Ling Yeh Sheng-Yow Ho Yuan-Hua Wu Bour-Jr Wang Wei-Jan Huang Yuan-Soon Ho Ying-Jan Wang Li-Ching Chen Shih-Hsin Tu |
| author_facet | Hui-Wen Chiu Ya-Ling Yeh Sheng-Yow Ho Yuan-Hua Wu Bour-Jr Wang Wei-Jan Huang Yuan-Soon Ho Ying-Jan Wang Li-Ching Chen Shih-Hsin Tu |
| author_sort | Hui-Wen Chiu |
| collection | DOAJ |
| description | Radiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC. |
| first_indexed | 2024-03-12T11:12:13Z |
| format | Article |
| id | doaj.art-064391714b2e4c29bb7751fc44b4b981 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T11:12:13Z |
| publishDate | 2019-11-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-064391714b2e4c29bb7751fc44b4b9812023-09-02T02:37:58ZengMDPI AGCancers2072-66942019-11-011111170310.3390/cancers11111703cancers11111703A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast CancerHui-Wen Chiu0Ya-Ling Yeh1Sheng-Yow Ho2Yuan-Hua Wu3Bour-Jr Wang4Wei-Jan Huang5Yuan-Soon Ho6Ying-Jan Wang7Li-Ching Chen8Shih-Hsin Tu9Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Radiation Oncology, Chi Mei Medical Center, Tainan 71004, TaiwanDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanDepartment of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 70101, TaiwanGraduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, TaiwanTMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, TaiwanDepartment of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, TaiwanTMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, TaiwanDivision of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, TaiwanRadiation therapy (RT) is one of the main treatments for triple-negative breast cancer (TNBC). However, many patients experience RT failure due to the metastatic potential of RT and the radiation resistance of several cancers. Histone deacetylase inhibitors (HDACis) can serve as radiosensitizers. In this study, we investigated whether a novel HDACi, TMU-35435, could reinforce radiosensitivity through the induction of misfolded protein aggregation and autophagy in TNBC. Significantly enhanced toxicity was found for the combination treatment compared with TMU-35435 or irradiation (IR) treatment alone in TNBC cells. The combination treatment induced misfolded protein aggregation and TMU-35435 inhibited the interaction of HDAC6 with dynein. Furthermore, the combined treatment induced endoplasmic reticulum (ER) stress but did not trigger apoptosis. In addition, the combination treatment caused autophagic cell death. Tumor growth in the mouse of model orthotopic breast cancer was suppressed by the combination treatment through the induction of ER stress and autophagy. These findings support the future evaluation of the novel HDACi TMU-35435, as a potent radiosensitizer in TNBC.https://www.mdpi.com/2072-6694/11/11/1703histone deacetylase inhibitoraggresomeradiationautophagytriple-negative breast cancer |
| spellingShingle | Hui-Wen Chiu Ya-Ling Yeh Sheng-Yow Ho Yuan-Hua Wu Bour-Jr Wang Wei-Jan Huang Yuan-Soon Ho Ying-Jan Wang Li-Ching Chen Shih-Hsin Tu A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer Cancers histone deacetylase inhibitor aggresome radiation autophagy triple-negative breast cancer |
| title | A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer |
| title_full | A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer |
| title_fullStr | A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer |
| title_full_unstemmed | A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer |
| title_short | A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer |
| title_sort | new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple negative breast cancer |
| topic | histone deacetylase inhibitor aggresome radiation autophagy triple-negative breast cancer |
| url | https://www.mdpi.com/2072-6694/11/11/1703 |
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