Journal
CANCERS
Volume 11, Issue 11, Pages -Publisher
MDPI
DOI: 10.3390/cancers11111703
Keywords
histone deacetylase inhibitor; aggresome; radiation; autophagy; triple-negative breast cancer
Categories
Funding
- Ministry of Science and Technology, Taiwan [MOST 105-2320-B-038-021-MY3, MOST106-2314-B-038-053-MY3, MOST 106-2314-B-006-029-MY3, MOST106-2320-B-038-061-MY3, MOST108-2320-B-038-033-MY3, MOST108-2320-B-038-002]
- Taipei Medical University [TMU104-AE1-B12]
- Health and Welfare Surcharge of Tobacco Products grant [MOHVV108-TDU-B-212-124014]
- TMU Research Center of Cancer Translational Medicine from The Featured Areas Research Center Program
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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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