Arsenic trioxide (As(2)O(3)) induces apoptosis through activation of Bax in hematopoietic cells.
This study explores the roles of Bax and other Bcl-2 family members play in arsenic trioxide (As(2)O(3))-induced apoptosis. We showed that As(2)O(3) 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 As(2)O(3). Stable overexpression of Bcl-2 in IM-9 cells (IM-9/Bcl-2) inhibited As(2)O(3)-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 As(2)O(3) were not inhibited by the pancaspase inhibitor z-VAD-fmk, although Bid cleavage could be completely abolished. Bax activation by As(2)O(3) seemed to require stress-induced intracellular 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 As(2)O(3) 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.
Zheng
Yanhua
Y
The Laboratory of Apoptosis and Cancer Biology, The National Key Laboratory of Biomembrane and Membrane Biotechnology, The Institute of Zoology, Chinese Academy of Sciences, Beijing 100080, People's Republic of China.
Yamaguchi
Hirohito
H
Tian
Changhai
C
Lee
Michael W
MW
Tang
Hong
H
Wang
Hong-Gang
HG
Chen
Quan
Q
D017304:Annexin A5 / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D017209:Apoptosis; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D004396:Coloring Agents / Q000494:pharmacology; D003600:Cytosol / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004789:Enzyme Activation; D006412:Hematopoietic Stem Cells / Q000378:metabolism*; D006801:Humans; D019169:Jurkat Cells; D008928:Mitochondria / Q000378:metabolism; D010087:Oxides / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry; D011487:Protein Conformation; D021381:Protein Transport; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D017382:Reactive Oxygen Species; D013347:Subcellular Fractions / Q000378:metabolism; D013997:Time Factors; D051028:bcl-2-Associated X Protein
D017304:Annexin A5; D000970:Antineoplastic Agents; D001152:Arsenicals; C494826:BAX protein, human; D004396:Coloring Agents; D010087:Oxides; D010455:Peptides; D019253:Proto-Oncogene Proteins c-bcl-2; D017382:Reactive Oxygen Species; D051028:bcl-2-Associated X Protein; D000077237:Arsenic Trioxide