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

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57 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 languageEnglish (US)
Pages (from-to)3339-3347
Number of pages9
JournalOncogene
Volume24
Issue number20
DOIs
StatePublished - May 5 2005

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Keywords

  • Apoptosis
  • Arsenic trioxide
  • Bax
  • Mitochondria
  • Reactive oxygen species

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

Cite this

Zheng, Y., Yamaguchi, H., Tian, C., Lee, M. W., Tang, H., Wang, H. G., & Chen, Q. (2005). Arsenic trioxide (As2O3) induces apoptosis through activation of Bax in hematopoietic cells. Oncogene, 24(20), 3339-3347. https://doi.org/10.1038/sj.onc.1208484