Antimony trioxide-induced apoptosis is dependent on SEK1/JNK signaling.
Very little is known concerning the toxicity of antimony, despite its commercial use as a flame retardant and medical use as a treatment for parasitic infections. Our previous studies show that antimony trioxide (Sb(2)O(3)) induces growth inhibition in patient-derived acute promyelocytic leukemia (APL) cell lines, a disease in which a related metal, arsenic trioxide (As(2)O(3)), is used clinically. However, signaling pathways initiated by Sb(2)O(3) treatment remain undefined. Here, we show that Sb(2)O(3) treatment of APL cells is associated with increased apoptosis as well as differentiation markers. Sb(2)O(3)-induced reactive oxygen species (ROS) correlated with increased apoptosis. In addition, when we decreased the buffering capacity of the cell by depleting glutathione, ROS production and apoptosis was enhanced. Arsenic-resistant APL cells with increased glutathione levels exhibited increased cross-resistance to Sb(2)O(3). Based on studies implicating c-jun kinase (JNK) in the mediation of the response to As(2)O(3), we investigated the role for JNK in Sb(2)O(3)-induced apoptosis. Sb(2)O(3) activates JNK and its downstream target, AP-1. In fibroblasts with a genetic deletion in SEK1, an upstream regulator of JNK, Sb(2)O(3)-induced growth inhibition as well as JNK activation was decreased. These data suggest roles for ROS and the SEK1/JNK pathway in the cytotoxicity associated with Sb(2)O(3) exposure.
Mann
Koren K
KK
Montreal Centre for Experimental Therapeutics in Cancer and Lady Davis Institute for Medical Research, SMBD Jewish General Hospital, Canada.
Davison
Kelly
K
Colombo
Myrian
M
Colosimo
April L
AL
Diaz
Zuanel
Z
Padovani
Alessandra M S
AM
Guo
Qi
Q
Scrivens
P James
PJ
Gao
Wenli
W
Mader
Sylvie
S
Miller
Wilson H
WH
D000965:Antimony / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects*; D006367:HeLa Cells; D006801:Humans; D048670:MAP Kinase Kinase 4 / Q000378:metabolism*; D048055:Mitogen-Activated Protein Kinase 8 / Q000378:metabolism*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism
D017382:Reactive Oxygen Species; D018808:Transcription Factor AP-1; D000965:Antimony; D048055:Mitogen-Activated Protein Kinase 8; D048670:MAP Kinase Kinase 4; C037554:antimony trioxide