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  3. A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer

A New Histone Deacetylase Inhibitor Enhances Radiation Sensitivity through the Induction of Misfolded Protein Aggregation and Autophagy in Triple-Negative Breast Cancer

  • Cancers (Basel). 2019 Nov 1;11(11):1703. doi: 10.3390/cancers11111703.
Hui-Wen Chiu 1 2,  Ya-Ling Yeh 3,  Sheng-Yow Ho 4 5,  Yuan-Hua Wu 6 7,  Bour-Jr Wang 8 9,  Wei-Jan Huang 10,  Yuan-Soon Ho 11 12 13 14,  Ying-Jan Wang 15,  Li-Ching Chen 16 17 18,  Shih-Hsin Tu 19 20 21
Affiliations

Affiliations

  • 1 Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. leu3@tmu.edu.tw.
  • 2 Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, Taipei Medical University, Taipei 11031, Taiwan. leu3@tmu.edu.tw.
  • 3 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. linn7627@hotmail.com.
  • 4 Department of Radiation Oncology, Chi Mei Medical Center, Tainan 71004, Taiwan. shengho@seed.net.tw.
  • 5 Graduate Institute of Medical Sciences, Chang Jung Christian University, Tainan 71101, Taiwan. shengho@seed.net.tw.
  • 6 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. wuyh@mail.ncku.edu.tw.
  • 7 Department of Radiation Oncology, National Cheng Kung University Hospital, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. wuyh@mail.ncku.edu.tw.
  • 8 Department of Occupational and Environmental Medicine, National Cheng Kung University Hospital, Tainan 70101, Taiwan. pochih.wang@msa.hinet.net.
  • 9 Department of Cosmetic Science and Institute of Cosmetic Science, Chia Nan University of Pharmacy and Science, Tainan 71710, Taiwan. pochih.wang@msa.hinet.net.
  • 10 Graduate Institute of Pharmacognosy, Taipei Medical University, Taipei 11031, Taiwan. wjhuang@tmu.edu.tw.
  • 11 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan. hoyuansn@tmu.edu.tw.
  • 12 Graduate Institute of Medical Sciences, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. hoyuansn@tmu.edu.tw.
  • 13 Department of Laboratory Medicine, Taipei Medical University Hospital, Taipei 11031, Taiwan. hoyuansn@tmu.edu.tw.
  • 14 School of Medical Laboratory Science and Biotechnology, College of Medical Science and Technology, Taipei Medical University, Taipei 11031, Taiwan. hoyuansn@tmu.edu.tw.
  • 15 Department of Environmental and Occupational Health, College of Medicine, National Cheng Kung University, Tainan 70101, Taiwan. yjwang@mail.ncku.edu.tw.
  • 16 TMU Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei 11031, Taiwan. lcchen@tmu.edu.tw.
  • 17 Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan. lcchen@tmu.edu.tw.
  • 18 Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. lcchen@tmu.edu.tw.
  • 19 Division of Breast Surgery, Department of Surgery, Taipei Medical University Hospital, Taipei 11031, Taiwan. drtu@h.tmu.edu.tw.
  • 20 Taipei Cancer Center, Taipei Medical University, Taipei 11031, Taiwan. drtu@h.tmu.edu.tw.
  • 21 Department of Surgery, School of Medicine, College of Medicine, Taipei Medical University, Taipei 11031, Taiwan. drtu@h.tmu.edu.tw.
PMID: 31683883 DOI: 10.3390/cancers11111703
Abstract

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.

Keywords

aggresome; autophagy; histone deacetylase inhibitor; radiation; triple-negative breast cancer.

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