A synthetic chalcone, 2′-hydroxy-2,3,5′-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells
A synthetic chalcone, 2′-hydroxy-2,3,5′-trimethoxychalcone triggers unfolded protein response-mediated apoptosis in breast cancer cells
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DOI：
10.1016/j.canlet.2015.12.017
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发表时间：
2016-03-01
期刊：
影响因子：
9.7
通讯作者：
Shin, Soon Young
中科院分区：
文献类型：
--
作者：
Lee, Da Hyun;Jung, You Jung;Shin, Soon Young
本研究的主要目的是寻找有效预防乳腺癌的新型化学制剂。内质网应激可通过未折叠蛋白反应（UPR）诱导细胞凋亡。2'-羟基-2,3,5'-三甲氧基查尔酮（DK143）是一种人工合成的类黄酮衍生物。本研究提供了支持UPR在介导DK143凋亡作用中的作用的证据。DK143通过激活MDA-MB-231乳腺癌细胞的caspase通路触发凋亡，而不影响MCF10A非转化乳腺上皮细胞的活力。进一步分析发现，DK143在MDA-MB-231细胞中产生活性氧（ROS），而在MCF10A细胞中不产生，并上调MDA-MB-231细胞中内质网应激传感器的表达，包括GRP78/BiP、IRE1 α、CHOP和Bim。此外，DK143还激活了与uprr相关的转录因子XBP-1和CHOP。此外，通过相应的siRNA分子沉默IRE1 α或CHOP可减弱dk143诱导的细胞凋亡。此外，DK143在体内抑制小鼠肿瘤生长。这些结果表明，通过UPR诱导促进乳腺癌细胞内质网应激可能是开发新的乳腺癌化疗或化学预防药物的一种有前途的策略。2015爱思唯尔爱尔兰有限公司版权所有。
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.