A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer

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

研究成果: 雜誌貢獻文章

摘要

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.

原文英語
文章編號1703
期刊Cancers
11
發行號11
DOIs
出版狀態已發佈 - 十一月 1 2019

指紋

Triple Negative Breast Neoplasms
Histone Deacetylase Inhibitors
Radiation Tolerance
Autophagy
Proteins
Endoplasmic Reticulum Stress
Radiotherapy
Therapeutics
Dyneins
Neoplasms
Radiation
Apoptosis
Breast Neoplasms
Growth

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

引用此文

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title = "A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer",
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.",
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author = "Chiu, {Hui Wen} and Yeh, {Ya Ling} and Ho, {Sheng Yow} and Wu, {Yuan Hua} and Wang, {Bour Jr} and Huang, {Wei Jan} and Ho, {Yuan Soon} and Wang, {Ying Jan} and Chen, {Li Ching} and Tu, {Shih Hsin}",
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T1 - A new histone deacetylase inhibitor enhances radiation sensitivity through the induction of misfolded protein aggregation and autophagy in triple-negative breast cancer

AU - Chiu, Hui Wen

AU - Yeh, Ya Ling

AU - Ho, Sheng Yow

AU - Wu, Yuan Hua

AU - Wang, Bour Jr

AU - Huang, Wei Jan

AU - Ho, Yuan Soon

AU - Wang, Ying Jan

AU - Chen, Li Ching

AU - Tu, Shih Hsin

PY - 2019/11/1

Y1 - 2019/11/1

N2 - 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.

AB - 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.

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KW - Histone deacetylase inhibitor

KW - Radiation

KW - Triple-negative breast cancer

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