Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells

Inik Chang, Shahana Majid, Sharanjot Saini, Mohd S. Zaman, Soichiro Yamamura, Takeshi Chiyomaru, Varahram Shahryari, Shinichiro Fukuhara, Guoren Deng, Rajvir Dahiya, Yuichiro Tanaka

Research output: Contribution to journalArticle

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-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.

Original languageEnglish (US)
Pages (from-to)1049-1059
Number of pages11
JournalMolecular cancer therapeutics
Volume12
Issue number6
DOIs
StatePublished - Jun 1 2013
Externally publishedYes

Fingerprint

Prostatic Neoplasms
Mitogen-Activated Protein Kinase 9
bcl-2 Homologous Antagonist-Killer Protein
Apoptosis
Mitochondria
Proteins
Neoplasms
2-methoxyestradiol
Mitochondrial Membrane Potential
Caspases
Cytochromes c
Antineoplastic Agents
Estrogens
Messenger RNA

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

Cite this

Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells. / Chang, Inik; Majid, Shahana; Saini, Sharanjot; Zaman, Mohd S.; Yamamura, Soichiro; Chiyomaru, Takeshi; Shahryari, Varahram; Fukuhara, Shinichiro; Deng, Guoren; Dahiya, Rajvir; Tanaka, Yuichiro.

In: Molecular cancer therapeutics, Vol. 12, No. 6, 01.06.2013, p. 1049-1059.

Research output: Contribution to journalArticle

Chang, I, Majid, S, Saini, S, Zaman, MS, Yamamura, S, Chiyomaru, T, Shahryari, V, Fukuhara, S, Deng, G, Dahiya, R & Tanaka, Y 2013, 'Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells', Molecular cancer therapeutics, vol. 12, no. 6, pp. 1049-1059. https://doi.org/10.1158/1535-7163.MCT-12-1187
Chang, Inik ; Majid, Shahana ; Saini, Sharanjot ; Zaman, Mohd S. ; Yamamura, Soichiro ; Chiyomaru, Takeshi ; Shahryari, Varahram ; Fukuhara, Shinichiro ; Deng, Guoren ; Dahiya, Rajvir ; Tanaka, Yuichiro. / Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells. In: Molecular cancer therapeutics. 2013 ; Vol. 12, No. 6. pp. 1049-1059.
@article{4042b48caa364079a3cadde10e2b1672,
title = "Hrk mediates 2-methoxyestradiol-induced mitochondrial apoptotic signaling in prostate cancer cells",
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-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.",
author = "Inik Chang and Shahana Majid and Sharanjot Saini and Zaman, {Mohd S.} and Soichiro Yamamura and Takeshi Chiyomaru and Varahram Shahryari and Shinichiro Fukuhara and Guoren Deng and Rajvir Dahiya and Yuichiro Tanaka",
year = "2013",
month = "6",
day = "1",
doi = "10.1158/1535-7163.MCT-12-1187",
language = "English (US)",
volume = "12",
pages = "1049--1059",
journal = "Molecular Cancer Therapeutics",
issn = "1535-7163",
publisher = "American Association for Cancer Research Inc.",
number = "6",

}

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 - 2013/6/1

Y1 - 2013/6/1

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.

UR - http://www.scopus.com/inward/record.url?scp=84879283390&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84879283390&partnerID=8YFLogxK

U2 - 10.1158/1535-7163.MCT-12-1187

DO - 10.1158/1535-7163.MCT-12-1187

M3 - Article

C2 - 23580416

AN - SCOPUS:84879283390

VL - 12

SP - 1049

EP - 1059

JO - Molecular Cancer Therapeutics

JF - Molecular Cancer Therapeutics

SN - 1535-7163

IS - 6

ER -