ASK1 is activated by arsenic trioxide in leukemic cells through accumulation of reactive oxygen species and may play a negative role in induction of apoptosis.
Arsenic trioxide (ATO) is remarkably effective for treating acute promyelocytic leukemia. Here, we find that ATO treatment of NB4 and K562 leukemic cells induces activation of ASK1. ASK1 activation was induced most significantly at low concentrations of ATO, where G2/M arrest but not apoptosis was induced. On the other hand, ATO barely activated ASK1 at high concentrations, where apoptosis as well as activation of JNK and p38 was induced significantly. ATO-induced accumulation of reactive oxygen species (ROS), while the ASK1 activation was suppressed by cotreatment with an antioxidant, N-acetyl-l-cysteine. Murine embryonic fibroblasts (MEFs) from ASK1-deficient mice were more susceptible to ATO-induced apoptosis than control MEFs. Furthermore, ATO at the low concentration induced significant apoptosis in K562 cells when ASK1 was knocked down by siRNA. These results indicate that ASK1 is activated by ATO through ROS accumulation and may negatively regulate apoptosis in leukemic cells without activating p38 and JNK.
Yan
Weihua
W
Department of Hematology, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyoku, Tokyo 113-8519, Japan.
Arai
Ayako
A
Aoki
Mae
M
Ichijo
Hidenori
H
Miura
Osamu
O
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D000077237:Arsenic Trioxide; D001152:Arsenicals / Q000494:pharmacology*; D002460:Cell Line; D004789:Enzyme Activation / Q000187:drug effects; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D007938:Leukemia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*; D048848:MAP Kinase Kinase Kinase 5 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D010087:Oxides / Q000494:pharmacology*; D034741:RNA, Small Interfering / Q000235:genetics; D017382:Reactive Oxygen Species / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
D001152:Arsenicals; D010087:Oxides; D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048848:MAP Kinase Kinase Kinase 5; D000077237:Arsenic Trioxide