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.
|Number of pages||9|
|State||Published - May 5 2005|
Bibliographical noteFunding 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.
- Arsenic trioxide
- Reactive oxygen species
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research