期刊
FREE RADICAL BIOLOGY AND MEDICINE
卷 67, 期 -, 页码 159-170出版社
ELSEVIER SCIENCE INC
DOI: 10.1016/j.freeradbiomed.2013.10.004
关键词
Arctigenin; Phytoestrogen; Apoptosis; Oxidative stress; Epigenetic; Breast cancer; Free radicals
资金
- National Science Council of Taiwan [NSC 102-2632-B-037-001-MY3, NSC 99-2320-B-037-017-MY3]
- Excellence for Cancer Research Center grant, Department of Health, Executive Yuan, Taipei, Taiwan [DOH102-TD-C-111-002]
- Kaohsiung Medical University Research Foundation [KMUER008]
- Kaohsiung Medical University Hospital Research Foundation [KMUH 98-8G03, KMUH9836, 10034]
This study investigates the anticancer effect of arctigenin (ATG), a natural lignan product of Arctium lappa L, in human breast cancer MDA-MB-231 cells. Results indicate that ATG inhibits MDA-MB-231 cell growth by inducing apoptosis in vitro and in vivo. ATG triggers the mitochondria] caspase-independent pathways, as indicated by changes in Bax/Bcl-2 ratio, resulting in AIF and EndoG nuclear translocation. ATG increased cellular reactive oxygen species (ROS) production by increasing p22(phox)/NADPH oxidase 1 interaction and decreasing glutathione level. ATG clearly increases the activation of p38 MAPK, but not JNK and ERK1/2. Antioxidant EUK-8, a synthetic catalytic superoxide and hydrogen peroxide scavenger, significantly decreases ATG-mediated p38 activation and apoptosis. Blocking p38 with a specific inhibitor suppresses ATG-mediated Bcl-2 downregulation and apoptosis. Moreover, ATG activates ATF-2, a transcription factor activated by p38, and then upregulates histone H3K9 trimethylation in the Bcl-2 gene promoter region, resulting in Bcl-2 downregulation. Taken together, the results demonstrate that ATG induces apoptosis of MDA-MB-231 cells via the ROS/p38 MAPK pathway and epigenetic regulation of Bcl-2 by upregulation of histone H3K9 trimethylation. Crown Copyright (C) 2013 Published by Elsevier Inc. All rights reserved.
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