Journal
CANCER LETTERS
Volume 372, Issue 1, Pages 1-9Publisher
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2015.12.017
Keywords
2 '-Hydroxy-2,3,5 '-trimethoxychalcone; Reactive oxygen species; Unfolded protein response; Caspase; Apoptosis; Breast cancer
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Funding
- National Research Foundation of Korea (NRF) - Ministry of Education [2013R1A1A2060273]
- KU Research Professor Program of Konkuk University
- National Research Foundation of Korea [2013R1A1A2060273] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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The primary aim of this study was to find novel chemopreventive agents effective against breast cancer. Endoplasmic reticulum (ER) stress can induce apoptosis through the unfolded protein response (UPR). 2'-Hydroxy-2,3,5'-trimethoxychalcone (DK143) is a synthetic flavonoid derivative. The present study provides evidence supporting the role of the UPR in mediating the apoptotic effect of DK143. Treatment with DK143 triggered apoptosis through the activation of the caspase pathway in MDA-MB-231 breast cancer cells without affecting viability of MCF10A non-transformed breast epithelial cells. Further analysis revealed that DK143 produced reactive oxygen species (ROS) in MDA-MB-231 cells, but not in MCF10A cells, and upregulated the expression of ER stress sensors, including GRP78/BiP, IRE1 alpha, CHOP, and Bim in MDA-MB-231 cells. In addition, UPR-related transcription factors, XBP-1 and CHOP, were activated by DK143. Moreover, silencing of IRE1 alpha or CHOP by corresponding siRNA molecules attenuated DK143-induced apoptosis. Furthermore, DK143 suppressed mouse tumor growth in vivo. These results demonstrate that promoting ER stress in breast cancer cells via UPR induction might be a promising strategy for developing new chemotherapeutic or chemopreventive agents for breast cancer. (C) 2015 Elsevier Ireland Ltd. All rights reserved.
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