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| 標題: | A novel histone deacetylase inhibitor TMU-35435 enhances etoposide cytotoxicity through the proteasomal degradation of DNA-PKcs in triple-negative breast cancer |
| 作者: | Wu, Yuan-Hua
Hong, Chi-Wei
Wang, Yi-Ching
Huang, Wei-Jan
Yeh, Ya-Ling
Wang, Bour-Jr
Wang, Ying-Jan
Chiu, Hui-Wen |
| 貢獻者: | Natl Cheng Kung Univ, Coll Med, Dept Environm & Occupat Hlth
Natl Cheng Kung Univ, Coll Med,Natl Cheng Kung Univ Hosp, Dept Radiat Oncol
Natl Cheng Kung Univ, Dept Pharmacol
Natl Cheng Kung Univ, Inst Basic Med Sci
Taipei Med Univ, Grad Inst Pharmacognosy
Natl Cheng Kung Univ Hosp, Dept Occupat & Environm Med
Chia Nan Univ Pharm & Sci, Dept Cosmet Sci
Chia Nan Univ Pharm & Sci, Inst Cosmet Sci
Asia Univ, Dept Biomed Informat
China Med Univ,China Med Univ Hosp, Dept Med Res
Taipei Med Univ, Coll Med, Grad Inst Clin Med
Taipei Med Univ, Shuang Ho Hosp, Dept Internal Med |
| 關鍵字: | DNA damage
DNA repair
Ubiquitin-proteasome system
Triple-negative breast cancer |
| 日期: | 2017-08-01 |
| 上傳時間: | 2018-11-30 15:50:09 (UTC+8) |
| 出版者: | Elsevier Ireland Ltd |
| 摘要: | Triple-negative breast cancer (TNBC) treatment offers only limited benefits, and it is very relevant given the significant number of deaths that it causes. DNA repair pathways can enable tumor cells to survive DNA damage that is induced by chemotherapeutic or radiation treatments. Histone deacetylase inhibitors (HDACi) inhibited DNA repair proteins. However, the detailed mechanisms for this inhibition remain unclear. In the present study, we investigated whether a newly developed HDACi, TMU-35435, could enhance etoposide cytotoxicity by inhibiting DNA repair proteins in triple-negative breast cancer. We found synergistic cytotoxicity following treatment of 4T1 cells with etoposide and TMU-35435. Furthermore, TMU-35435 enhances etoposide-induced DNA damage by inhibiting the DNA repair pathway (non-homologous end joining, NHEJ). TMU-35435 suppresses the NHEJ pathway through the ubiquitination of DNA-dependent protein kinase catalytic subunit (DNA-PKcs). In addition, TMU-35435 ubiquitinated DNA-PKcs by inducing the interaction between RNF144A (an E3 ligase) and DNA-PKcs. The combined treatment induced apoptosis and autophagic cell death in 4T1 cells. In an orthotopic breast cancer model, combined treatment with TMU-35435 and etoposide showed anti-tumor growth through the increase of DNA damage and cell death. Taken together, our data suggest that TMU-35435 enhances etoposide cytotoxicity by regulating ubiquitin-proteasome system and inhibiting the DNA repair pathway in TNBC. (C) 2017 Elsevier B.V. All rights reserved. |
| 關聯: | Cancer Letters, v.400, pp.79-88 |
| 顯示於類別: | [化妝品應用與管理系(所)] 期刊論文
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