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

1Department of Urology, VA Medical Center and UCSF.
Molecular Cancer Therapeutics (Impact Factor: 5.68). 04/2013; 12(6). DOI: 10.1158/1535-7163.MCT-12-1187
Source: PubMed


Prostate cancer is one of the most prevalent cancers in males and ranks 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 Jun N-terminal 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 up-regulated by 2-ME, and Hrk induction is dependent on 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 pro-apoptotic protein Bak in this process suggested the possible interaction between Hrk and Bak. Thus, Hrk activation by 2-ME or its over-expression displaced Bak from the complex with anti-apoptotic protein Bcl-xL, while deletion of the Hrk BH3 domain abolished its interaction with Bcl-xL, reducing the pro-apoptotic function of Hrk. Finally, Hrk is also involved in the 2-ME-mediated reduction of X-linked inhibitor of apoptosis (XIAP) 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 pro-apoptotic protein Bak.

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    • "Control and HDAC1/2-Ablated Retinae After Injury JNK is a member of the mitogen-activated protein kinase family (also known as the stress-activated protein kinases or SAPKs) that is activated in response to a variety of cellular stresses. Sustained activation contributes to cell death through different targets including c-Jun (Whitfield et al., 2001; Ma et al., 2007, p. 53; Fuchs et al., 1998a, 1998b) and Hrk (Chang et al., 2013). Previous studies have demonstrated that JNK signaling and its target transcription factor c-Jun are activated in RGCs following optic nerve injury. "
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