Cellular Iron Depletion Stimulates the JNK and p38 MAPK Signaling Transduction Pathways, Dissociation of ASK1-Thioredoxin, and Activation of ASK1

Iron Metabolism and Chelation Program, Department of Pathology and Bosch Institute, University of Sydney, Sydney, New South Wales 2006, Australia.
Journal of Biological Chemistry (Impact Factor: 4.57). 03/2011; 286(17):15413-27. DOI: 10.1074/jbc.M111.225946
Source: PubMed


The role of signaling pathways in the regulation of cellular iron metabolism is becoming increasingly recognized. Iron chelation is used for the treatment of iron overload but also as a potential strategy for cancer therapy, because iron depletion results in cell cycle arrest and apoptosis. This study examined potential signaling pathways affected by iron depletion induced by desferrioxamine (DFO) or di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone (Dp44mT). Both chelators affected multiple molecules in the mitogen-activated protein kinase (MAPK) pathway, including a number of dual specificity phosphatases that directly de-phosphorylate MAPKs. Examination of the phosphorylation of major MAPKs revealed that DFO and Dp44mT markedly increased phosphorylation of stress-activated protein kinases, JNK and p38, without significantly affecting the extracellular signal-regulated kinase (ERK). Redox-inactive DFO-iron complexes did not affect phosphorylation of JNK or p38, whereas the redox-active Dp44mT-iron complex significantly increased the phosphorylation of these kinases similarly to Dp44mT alone. Iron or N-acetylcysteine supplementation reversed Dp44mT-induced up-regulation of phospho-JNK, but only iron was able to reverse the effect of DFO on JNK. Both iron chelators significantly reduced ASK1-thioredoxin complex formation, resulting in the increased phosphorylation of ASK1, which activates the JNK and p38 pathways. Thus, dissociation of ASK1 could serve as an important signal for the phosphorylation of JNK and p38 activation observed after iron chelation. Phosphorylation of JNK and p38 likely play an important role in mediating the cell cycle arrest and apoptosis induced by iron depletion.

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    • "In good accordance with our results, mRNA expression studies with the thiosemicarbazone Dp44mT (di-2-pyridylketone-4,4,- dimethyl-3-thiosemicarbazone) suggested that iron depletion is responsible for elevated levels of DITT3 (a synonym for the gene encoding CHOP) (Yu and Richardson, 2011). Indeed, investigations regarding the stability of metal complexes of 3-AP and 3-AP-Me with iron, zinc, and copper revealed that terminally dimethylated thiosemicarbazones, such as 3-AP-Me, form metal complexes with higher stability (Enyedy et al., 2010, 2011). "
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