Involvement of p38 MAP kinase during iron chelator-mediated apoptotic cell death.
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.
Kim
Beom-Su
BS
Department of Microbiology and Immunology, Wonkwang Medical Science Institute, Iksan, Chonbuk 570-749, South Korea.
Yoon
Kwon-Ha
KH
Oh
Hyun-Mee
HM
Choi
Eun-Young
EY
Kim
Sang-Wook
SW
Han
Weon-Cheol
WC
Kim
Eun-A
EA
Choi
Suck-Chei
SC
Kim
Tae-Hyeon
TH
Yun
Ki-Jung
KJ
Kim
Eun-Cheol
EC
Lyou
June-Hyung
JH
Nah
Yong-Ho
YH
Chung
Hun-Taeg
HT
Cha
Young-Nam
YN
Jun
Chang-Duk
CD
D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases / Q000378:metabolism; D003574:Cytochrome c Group / Q000378:metabolism; D003676:Deferoxamine / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018922:HL-60 Cells; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D007425:Intracellular Membranes / Q000187:drug effects / Q000502:physiology; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism*; D007502:Iron Chelating Agents / Q000494:pharmacology*; D019169:Jurkat Cells / Q000201:enzymology / Q000378:metabolism; D008564:Membrane Potentials / Q000187:drug effects / Q000502:physiology; D051379:Mice; D008928:Mitochondria / Q000187:drug effects / Q000502:physiology; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D011725:Pyridines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases
D003574:Cytochrome c Group; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007502:Iron Chelating Agents; D011725:Pyridines; D007501:Iron; D020928:Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505530:CASP8 protein, human; C506433:CASP9 protein, human; C505409:Casp3 protein, mouse; C505526:Casp8 protein, mouse; C506434:Casp9 protein, mouse; D053148:Caspase 3; D053181:Caspase 8; D053453:Caspase 9; D020169:Caspases; D003676:Deferoxamine; C093642:SB 203580