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Involvement of p38 MAP kinase during iron chelator-mediated apoptotic cell death
Beom-Su Kim1, Kwon-Ha Yoon, Hyun-Mee Oh
1Department of Microbiology and Immunology, Wonkwang Medical Science Institute, Iksan, Chonbuk 570-749, South Korea.
Abstract:
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.
Insights
Iron chelators induce cancer cell death by activating p38 MAP kinase, a key mediator in the apoptosis pathway. This research highlights p38 MAP kinase
Area of Science:
- Molecular Biology
- Cell Biology
- Cancer Research
Background:
- Iron is crucial for neoplastic cell growth.
- Iron chelators are investigated for anti-cancer properties.
- The precise mechanisms of iron chelator-induced cell death are not fully understood.
Purpose of the Study:
- To elucidate the role of mitogen-activated protein (MAP) kinase pathways in apoptosis induced by iron chelators.
- To identify the specific MAP kinase subfamily mediating iron chelator-induced cell death.
Main Methods:
- Treatment of HL-60 cells with deferoxamine (DFO), an iron chelator.
- Analysis of MAP kinase subfamily activation (p38, ERK, JNK/SAPK).
- Assessment of cell death using MAP kinase inhibitors, specifically SB203580 (p38 inhibitor).
- Evaluation of mitochondrial cytochrome c release and caspase activation (caspase 3 and 8).
Main Results:
- Deferoxamine (DFO) activated p38 MAP kinase and ERK early, and JNK/SAPK late.
- The p38 MAP kinase inhibitor SB203580 protected HL-60 cells from DFO-induced death.
- DFO induced cytochrome c release and caspase activation, which were abolished by SB203580.
- p38 MAP kinase activation is a critical event in iron chelator-induced apoptosis.
Conclusions:
- p38 MAP kinase is a major mediator of apoptosis induced by iron chelators in HL-60 cells.
- Iron chelator-induced cell death involves the activation of a downstream apoptotic cascade initiated by p38 MAP kinase.
- Targeting the p38 MAP kinase pathway may offer a therapeutic strategy against cancers dependent on iron.