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Hrk Mediates 2-Methoxyestradiol–Induced Mitochondrial Apoptotic Signaling in Prostate Cancer Cells

Authors
 Guoren Deng ; Rajvir Dahiya ; Shinichiro Fukuhara ; Varahram Shahryari ; Takeshi Chiyomaru ; Soichiro Yamamura ; Mohd S. Zaman ; Sharanjot Saini ; Shahana Majid ; Inik Chang ; Yuichiro Tanaka 
Citation
 Molecular Cancer Therapeutics, Vol.12(6) : 1049~1059, 2013 
Journal Title
 Molecular Cancer Therapeutics 
ISSN
 1535-7163 
Issue Date
2013
Abstract
Prostate cancer is one of the most prevalent cancers in males and ranks as the second most common cause of cancer-related deaths. 2-methoxyestradiol (2-ME), an endogenous estrogen metabolite, is a promising anticancer agent for various types of cancers. Although 2-ME has been shown to activate c-Jun-NH2-kinase (JNK) and mitochondrial-dependent apoptotic signaling pathways, the underlying mechanisms, including downstream effectors, remain unclear. Here, we report that the human Bcl-2 homology 3 (BH3)-only protein harakiri (Hrk) is a critical effector of 2-ME-induced JNK/mitochondria-dependent apoptosis in prostate cancer cells. Hrk mRNA and protein are preferentially upregulated by 2-ME, and Hrk induction is dependent on the JNK activation of c-Jun. Hrk knockdown prevents 2-ME-mediated apoptosis by attenuating the decrease in mitochondrial membrane potential, subsequent cytochrome c (cyt c) release, and caspase activation. Involvement of the proapoptotic protein Bak in this process suggested the possible interaction between Hrk and Bak. Thus, Hrk activation by 2-ME or its overexpression displaced Bak from the complex with antiapoptotic protein Bcl-xL, whereas deletion of the Hrk BH3 domain abolished its interaction with Bcl-xL, reducing the proapoptotic function of Hrk. Finally, Hrk is also involved in the 2-ME-mediated reduction of X-linked inhibitor of apoptosis through Bak activation in prostate cancer cells. Together, our findings suggest that induction of the BH3-only protein Hrk is a critical step in 2-ME activation of the JNK-induced apoptotic pathway, targeting mitochondria by liberating proapoptotic protein Bak.
URI
http://ir.ymlib.yonsei.ac.kr/handle/22282913/88575
DOI
10.1158/1535-7163.MCT-12-1187
Appears in Collections:
1. 연구논문 > 2. College of Dentistry > Dept. of Oral Biology
Yonsei Authors
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Link
 http://mct.aacrjournals.org/content/12/6/1049.long
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