Arsenic trioxide (As2O3) induces apoptosis through activation of Bax in hematopoietic cells

Yanhua Zheng; Hirohito Yamaguchi; Changhai Tian; Michael W. Lee; Hong Tang; Hong Gang Wang; Quan Chen

doi:10.1038/sj.onc.1208484

Arsenic trioxide (As₂O₃) induces apoptosis through activation of Bax in hematopoietic cells

Yanhua Zheng, Hirohito Yamaguchi, Changhai Tian, Michael W. Lee, Hong Tang, Hong Gang Wang, Quan Chen

Research output: Contribution to journal › Article › peer-review

64 Scopus citations

Abstract

This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As₂O₃)-induced apoptosis. We showed that As₂O₃ treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As₂O₃. Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As₂O₃-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As₂O₃ were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As₂O₃ seemed to require stress-induced intracelular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As₂O₃ might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.

Original language	English
Pages (from-to)	3339-3347
Number of pages	9
Journal	Oncogene
Volume	24
Issue number	20
DOIs	https://doi.org/10.1038/sj.onc.1208484
State	Published - May 5 2005

Bibliographical note

Funding Information:
We are grateful to Dr Alex Almasan (Department of Cancer Biology, Cleveland Clinic, USA) for his thoughtful comments. We wish to thank Mrs J Wang, Xiaohui Wang and Haijing Jin for their technical assistance. This work was supported by grants of the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2004CB720003) and National Outstanding Young Investigator Fellowship (No. 30325013) from NSFC awarded to QC, ‘Knowledge Innovation Key Project’ (Kscx2-sw-2010) of Chinese Academy of Sciences, and the National Outstanding Young Oversea Investigator Fellowship to H-GW (No. 30228010). H-GW is supported by National Cancer Center Grants CA82197 and CA90315.

Funding

We are grateful to Dr Alex Almasan (Department of Cancer Biology, Cleveland Clinic, USA) for his thoughtful comments. We wish to thank Mrs J Wang, Xiaohui Wang and Haijing Jin for their technical assistance. This work was supported by grants of the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2004CB720003) and National Outstanding Young Investigator Fellowship (No. 30325013) from NSFC awarded to QC, ‘Knowledge Innovation Key Project’ (Kscx2-sw-2010) of Chinese Academy of Sciences, and the National Outstanding Young Oversea Investigator Fellowship to H-GW (No. 30228010). H-GW is supported by National Cancer Center Grants CA82197 and CA90315.

Funders	Funder number
National Proprietary Research Program	2002CB513100, 2004CB720003, 30325013
National Childhood Cancer Registry – National Cancer Institute	R01CA082197
National Natural Science Foundation of China (NSFC)	Kscx2-sw-2010
Chinese Academy of Sciences	30228010
National Cancer Center	CA90315

Keywords

Apoptosis
Arsenic trioxide
Bax
Mitochondria
Reactive oxygen species

ASJC Scopus subject areas

Molecular Biology
Genetics
Cancer Research

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

Access to Document

10.1038/sj.onc.1208484

Cite this

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title = "Arsenic trioxide (As2O3) induces apoptosis through activation of Bax in hematopoietic cells",

abstract = "This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As2O3)-induced apoptosis. We showed that As2O3 treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As2O3. Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As2O3-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As2O3 were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As2O3 seemed to require stress-induced intracelular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As2O3 might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.",

keywords = "Apoptosis, Arsenic trioxide, Bax, Mitochondria, Reactive oxygen species",

author = "Yanhua Zheng and Hirohito Yamaguchi and Changhai Tian and Lee, {Michael W.} and Hong Tang and Wang, {Hong Gang} and Quan Chen",

note = "Funding Information: We are grateful to Dr Alex Almasan (Department of Cancer Biology, Cleveland Clinic, USA) for his thoughtful comments. We wish to thank Mrs J Wang, Xiaohui Wang and Haijing Jin for their technical assistance. This work was supported by grants of the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2004CB720003) and National Outstanding Young Investigator Fellowship (No. 30325013) from NSFC awarded to QC, {\textquoteleft}Knowledge Innovation Key Project{\textquoteright} (Kscx2-sw-2010) of Chinese Academy of Sciences, and the National Outstanding Young Oversea Investigator Fellowship to H-GW (No. 30228010). H-GW is supported by National Cancer Center Grants CA82197 and CA90315.",

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T1 - Arsenic trioxide (As2O3) induces apoptosis through activation of Bax in hematopoietic cells

AU - Zheng, Yanhua

AU - Yamaguchi, Hirohito

AU - Tian, Changhai

AU - Lee, Michael W.

AU - Tang, Hong

AU - Wang, Hong Gang

AU - Chen, Quan

N1 - Funding Information: We are grateful to Dr Alex Almasan (Department of Cancer Biology, Cleveland Clinic, USA) for his thoughtful comments. We wish to thank Mrs J Wang, Xiaohui Wang and Haijing Jin for their technical assistance. This work was supported by grants of the National Proprietary Research Program (973 program project, No. 2002CB513100 and 2004CB720003) and National Outstanding Young Investigator Fellowship (No. 30325013) from NSFC awarded to QC, ‘Knowledge Innovation Key Project’ (Kscx2-sw-2010) of Chinese Academy of Sciences, and the National Outstanding Young Oversea Investigator Fellowship to H-GW (No. 30228010). H-GW is supported by National Cancer Center Grants CA82197 and CA90315.

PY - 2005/5/5

Y1 - 2005/5/5

N2 - This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As2O3)-induced apoptosis. We showed that As2O3 treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As2O3. Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As2O3-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As2O3 were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As2O3 seemed to require stress-induced intracelular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As2O3 might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.

AB - This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As2O3)-induced apoptosis. We showed that As2O3 treatment triggered Bax conformational change and subsequent translocation from cytosol to mitochondria to form various multimeric homo-oligomers in IM-9 cells. On the other hand, human leukemic Jurkat cells deficient in Bax showed dramatically reduced apoptosis in response to As2O3. Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As2O3-mediated Bax activation and apoptosis, and this inhibition could be partially averted by cell-permeable Bid-Bcl-2 homology (BH)3 peptide. Meanwhile, Bax conformational change and oligomerization induced by As2O3 were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As2O3 seemed to require stress-induced intracelular reactive oxygen species (ROS), since the ROS scavengers (N-acetyl-L-cysteine and lipoic acid) could completely block the conformational change and translocation of Bax from cytosol to mitochondria. These data suggest that As2O3 might exert the cell killing in part by inducing Bax activation through a Bcl-2-suppressible pathway in hematopoietic cells that is caspase independent and intracellular ROS regulated.

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KW - Bax

KW - Mitochondria

KW - Reactive oxygen species

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