title: Arctigenin, a dietary phytoestrogen, induces apoptosis of estrogen receptor-negative breast cancer cells through the ROS/p38 MAPK pathway and epigenetic regulation.
abstract: 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 mitochondrial 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.
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Chia-Jung
authors.initials: CJ
authors.lastname: Hsieh
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan; Department of Medical Research, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Po-Lin
authors.initials: PL
authors.lastname: Kuo
authors.affiliation: Department of Chinese Medicine, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Ying-Chan
authors.initials: YC
authors.lastname: Hsu
authors.affiliation: Institute of Clinical Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Cancer Center, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan.
authors.forename: Ya-Fang
authors.initials: YF
authors.lastname: Huang
authors.affiliation: Center for Resources, Research, and Development, Kaohsiung Medical University, Kaohsiung 807, Taiwan; Department of Obstetrics & Gynecology, Kaohsiung Medical University Hospital, Kaohsiung 807, Taiwan. Electronic address: tsaieing@yahoo.com.
authors.forename: Eing-Mei
authors.initials: EM
authors.lastname: Tsai
authors.affiliation: Graduate Institute of Medicine, College of Medicine, Kaohsiung Medical University, Kaohsiung 807, Taiwan. Electronic address: hsuyl326@gmail.com.
authors.forename: Ya-Ling
authors.initials: YL
authors.lastname: Hsu
mesh_terms: D051698:Activating Transcription Factor 2 / Q000235:genetics / Q000378:metabolism; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D044127:Epigenesis, Genetic; D005029:Ethylenediamines / Q000494:pharmacology; D005260:Female; D005663:Furans / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism; D006801:Humans; D017705:Lignans / Q000494:pharmacology*; D042361:Mammary Glands, Human / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019255:NADPH Oxidases / Q000235:genetics / Q000378:metabolism; D009942:Organometallic Compounds / Q000494:pharmacology; D048789:Phytoestrogens / Q000494:pharmacology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000235:genetics / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism*; D011960:Receptors, Estrogen / Q000172:deficiency / Q000235:genetics; D015398:Signal Transduction; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics* / Q000378:metabolism
chemical_list: D051698:Activating Transcription Factor 2; D000975:Antioxidants; D005029:Ethylenediamines; D005663:Furans; D006657:Histones; D017705:Lignans; D009942:Organometallic Compounds; D048789:Phytoestrogens; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D011960:Receptors, Estrogen; C090577:N,N'-bis(salicylideneamino)ethane-manganese(II); D019255:NADPH Oxidases; C086986:CYBA protein, human; D048051:p38 Mitogen-Activated Protein Kinases; C071942:arctigenin
keywords: Apoptosis; Arctigenin; Breast cancer; Epigenetic; Free radicals; Oxidative stress; Phytoestrogen