TY - JOUR
T1 - Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells
AU - Chang, Inik
AU - Majid, Shahana
AU - Saini, Sharanjot
AU - Zaman, Mohd S.
AU - Yamamura, Soichiro
AU - Chiyomaru, Takeshi
AU - Shahryari, Varahram
AU - Fukuhara, Shinichiro
AU - Deng, Guoren
AU - Dahiya, Rajvir
AU - Tanaka, Yuichiro
PY - 2013/6
Y1 - 2013/6
N2 - 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-NH 2-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.
AB - 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-NH 2-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.
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U2 - 10.1158/1535-7163.MCT-12-1187
DO - 10.1158/1535-7163.MCT-12-1187
M3 - Article
C2 - 23580416
AN - SCOPUS:84879283390
SN - 1535-7163
VL - 12
SP - 1049
EP - 1059
JO - Molecular cancer therapeutics
JF - Molecular cancer therapeutics
IS - 6
ER -