Involvement of p38 MAP kinase during iron chelator-mediated apoptotic cell death

被引:47
作者
Kim, BS
Yoon, KH
Oh, HM
Choi, EY
Kim, SW
Han, WC
Kim, EA
Choi, SC
Kim, TH
Yun, KJ
Kim, EC
Lyou, JH
Nah, YH
Chung, HT
Cha, YN
Jun, CD [1 ]
机构
[1] Wonkwang Med Sci Inst, Dept Microbiol & Immunol, Chonbuk 570749, South Korea
[2] Wonkwang Med Sci Inst, Dept Radiol, Chonbuk 570749, South Korea
[3] Wonkwang Med Sci Inst, Dept Digest Res Unit, Chonbuk 570749, South Korea
[4] Wonkwang Univ, Sch Dent, Dept Pathol, Chonbuk 570749, South Korea
[5] Inha Univ, Coll Med, Nitr Oxide Radical Toxicol Res Ctr, Inchon 402751, South Korea
关键词
iron; deferoxamine; p38 MAP kinase; c-Jun N-terminal kinase/stress-activated protein kinase; extracellular signal-regulated kinase; caspase; 3; 8; cytochrome c;
D O I
10.1016/S0008-8749(03)00031-5
中图分类号
Q2 [细胞生物学];
学科分类号
071009 ; 090102 ;
摘要
Iron is an essential element for the neoplastic cell growth, and iron chelators have been tested for their potential anti-proliferative and cytotoxic effects. To determine the mechanism of cell death induced by iron chelators, we explored the pathways of the three structurally related mitogen-activated protein (MAP) kinase subfamilies during apoptosis induced by iron chelators. We report that the chelator deferoxamine (DFO) strongly activates both p38 MAP kinase and extracellular signal-regulated kinase (ERK) at an early stage of incubation, but slightly activates c-Jun N-terminal kinase/stress-activated protein kinase (JNK/SAPK) at a late stage of incubation. Among three MAP kinase blockers used, however, the selective p38 MAP kinase inhibitor SB203580 could only protect HL-60 cells from chelator-induced cell death, indicating that p38 MAP kinase serves as a major mediator of apoptosis induced by iron chelator. DFO also caused release of cytochrome c from mitochondria and induced activation of caspase 3 and caspase 8. Interestingly, treatment of HL-60 cells with SB203580 greatly abolished cytochrome c release, and activation of caspase 3 and caspase 8. Collectively, the current study reveals that p38 MAP kinase plays an important role in iron chelator-mediated cell death of HL-60 cells by activating downstream apoptotic cascade that executes cell death pathway. (C) 2003 Elsevier Science (USA). All rights reserved.
引用
收藏
页码:96 / 106
页数:11
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