Repression of the heavy ferritin chain increases the labile iron pool of human K562 cells

2001 ◽  
Vol 356 (2) ◽  
pp. 311-316 ◽  
Author(s):  
Or KAKHLON ◽  
Yosef GRUENBAUM ◽  
Z. Ioav CABANTCHIK
Keyword(s):  
K562 Cells ◽  
Transferrin Receptors ◽  
Labile Iron Pool ◽  
Labile Iron ◽  
Iron Pool ◽  
Antisense Construct

The role of ferritin in the modulation of the labile iron pool was examined by repressing the heavy subunit of ferritin in K562 cells transfected with an antisense construct. Repression of the heavy ferritin subunit evoked an increase in the chemical levels and pro-oxidant activity of the labile iron pool and, in turn, caused a reduced expression of transferrin receptors and increased expression of the light ferritin subunit

The Cellular Labile Iron Pool and Intracellular Ferritin in K562 Cells

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 2128-2134 ◽  
Author(s):  
Abraham M. Konijn ◽  
Hava Glickstein ◽  
Boris Vaisman ◽  
Esther G. Meyron-Holtz ◽  
Itzchak N. Slotki ◽  
...  
Keyword(s):  
Biological Effects ◽  
Ferritin Level ◽  
Regulatory Protein ◽  
Iron Chelation ◽  
K562 Cells ◽  
Iron Chelator ◽  
Labile Iron Pool ◽  
Cellular Iron ◽  
Labile Iron ◽  
Iron Pool

Abstract The labile iron pool (LIP) harbors the metabolically active and regulatory forms of cellular iron. We assessed the role of intracellular ferritin in the maintenance of intracellular LIP levels. Treating K562 cells with the permeant chelator isonicotinoyl salicylaldehyde hydrazone reduced the LIP from 0.8 to 0.2 μmol/L, as monitored by the metalo-sensing probe calcein. When cells were reincubated in serum-free and chelator-free medium, the LIP partially recovered in a complex pattern. The first component of the LIP to reappear was relatively small and occurred within 1 hour, whereas the second was larger and relatively slow to occur, paralleling the decline in intracellular ferritin level (t½= 8 hours). Protease inhibitors such as leupeptin suppressed both the changes in ferritin levels and cellular LIP recovery after chelation. The changes in the LIP were also inversely reflected in the activity of iron regulatory protein (IRP). The 2 ferritin subunits, H and L, behaved qualitatively similarly in response to long-term treatments with the iron chelator deferoxamine, although L-ferritin declined more rapidly, resulting in a 4-fold higher H/L-ferritin ratio. The decline in L-ferritin, but not H-ferritin, was partially attenuated by the lysosomotrophic agent, chloroquine; on the other hand, antiproteases inhibited the degradation of both subunits to the same extent. These findings indicate that, after acute LIP depletion with fast-acting chelators, iron can be mobilized into the LIP from intracellular sources. The underlying mechanisms can be kinetically analyzed into components associated with fast release from accessible cellular sources and slow release from cytosolic ferritin via proteolysis. Because these iron forms are known to be redox-active, our studies are important for understanding the biological effects of cellular iron chelation.

scholarly journals Repression of the heavy ferritin chain increases the labile iron pool of human K562 cells

2001 ◽  
Vol 356 (2) ◽  
pp. 311 ◽  
Author(s):  
Or KAKHLON ◽  
Yosef GRUENBAUM ◽  
Z. Ioav CABANTCHIK
Keyword(s):  
K562 Cells ◽  
Labile Iron Pool ◽  
Labile Iron ◽  
Iron Pool

scholarly journals The role of labile iron pool in cardiovascular diseases.

2004 ◽  
Vol 51 (2) ◽  
pp. 471-480 ◽  
Author(s):  
Marcin Kruszewski
Keyword(s):  
Cardiovascular Diseases ◽  
Ischemia Reperfusion Injury ◽  
Copper Ions ◽  
Ischemia Reperfusion ◽  
Cardiovascular Pathology ◽  
Labile Iron Pool ◽  
Labile Iron ◽  
Iron Pool ◽  
Cellular Components

Although multiple factors are associated with cardiovascular pathology, there is now an impressive body of evidence that free radicals and nonradical oxidants might cause a number of cardiovascular dysfunctions. Both direct damage to cellular components and/or oxidation of extracellular biomolecules, e.g. LDL, might be involved in the aetiology of cardiovascular diseases. The key molecules in this process seem to be iron and copper ions that catalyse formation of the highly reactive hydroxyl radical. Chelation of iron ions has a beneficial effect on the processes associated with the development of atherosclerosis and formation of post-ischemic lesions. These findings are indirectly supported by the increasing body of evidence that stored body iron plays a crucial role in pathogenesis of atherosclerosis and ischemia/reperfusion injury.

scholarly journals Cancer cell death induced by ferritins and the peculiar role of their labile iron pool

Oncotarget ◽  
2018 ◽  
Vol 9 (46) ◽  
pp. 27974-27984 ◽  
Author(s):  
Juan Carlos Cutrin ◽  
Diego Alberti ◽  
Caterina Bernacchioni ◽  
Silvia Ciambellotti ◽  
Paola Turano ◽  
...  
Keyword(s):  
Cell Death ◽  
Cancer Cell ◽  
Labile Iron Pool ◽  
Cancer Cell Death ◽  
Labile Iron ◽  
Iron Pool

Repression of ferritin expression increases the labile iron pool, oxidative stress, and short-term growth of human erythroleukemia cells

Blood ◽  
2001 ◽  
Vol 97 (9) ◽  
pp. 2863-2871 ◽  
Author(s):  
Or Kakhlon ◽  
Yosef Gruenbaum ◽  
Zvi Ioav Cabantchik
Keyword(s):  
Protein Expression ◽  
Protein Oxidation ◽  
Day Treatment ◽  
K562 Cells ◽  
Growth Stimulation ◽  
Labile Iron Pool ◽  
Protein Levels ◽  
Ferritin Synthesis ◽  
Labile Iron ◽  
Iron Pool

Abstract The role of ferritin expression on the labile iron pool of cells and its implications for the control of cell proliferation were assessed. Antisense oligodeoxynucleotides were used as tools for modulating the expression of heavy and light ferritin subunits of K562 cells. mRNA and protein levels of each subunit were markedly reduced by 2-day treatment with antisense probes against the respective subunit. Although the combined action of antisense probes against both subunits reduced their protein expression, antisense repression of one subunit led to an increased protein expression of the other. Antisense treatment led to a rise in the steady-state labile iron pool, a rise in the production of reactive oxygen species after pro-oxidative challenges and in protein oxidation, and the down-regulation of transferrin receptors. When compared to the repression of individual subunits, co-repression of each subunit evoked a more than additive increase in the labile iron pool and the extent of protein oxidation. These treatments had no detectable effects on the long-term growth of cells. However, repression of ferritin synthesis facilitated the renewal of growth and the proliferation of cells pre-arrested at the G1/S phase. Renewed cell growth was significantly less dependent on external iron supply when ferritin synthesis was repressed and its degradation inhibited by lysosomal antiproteases. This study provides experimental evidence that links the effect of ferritin repression on growth stimulation to the expansion of the labile iron pool.

scholarly journals The Role of Iron in the Pathogenesis of Atherosclerosis

2017 ◽  
pp. S55-S67 ◽  
Author(s):  
P. KRAML
Keyword(s):  
Cardiovascular Risk ◽  
Free Oxygen Radicals ◽  
Intracellular Iron ◽  
Iron Storage ◽  
Oxidation Stress ◽  
Iron Stores ◽  
Labile Iron Pool ◽  
Labile Iron ◽  
Iron Pool

Ferritin and increased iron stores first appeared on the list of cardiovascular risk factors more than 30 years ago and their causal role in the pathogenesis of atherosclerosis has been heavily discussed since the early 1990s. It seems that besides traditional factors such as hyperlipoproteinemia, hypertension, diabetes mellitus, obesity, physical inactivity, smoking and family history, high iron stores represent an additional parameter that could modify individual cardiovascular risk. The role of iron in the pathogenesis of atherosclerosis was originally primarily associated with its ability to catalyze the formation of highly reactive free oxygen radicals and the oxidation of atherogenic lipoproteins. Later, it became clear that the mechanism is more complex. Atherosclerosis is a chronic fibroproliferative inflammatory process and iron, through increased oxidation stress as well as directly, can control both native and adaptive immune responses. Within the arterial wall, iron affects all of the cell types that participate in the atherosclerotic process (monocytes/macrophages, endothelial cells, vascular smooth muscle cells and platelets). Most intracellular iron is bound in ferritin, whereas redox-active iron forms labile iron pool. Pro-inflammatory and anti-inflammatory macrophages within arterial plaque differ with regard to the amount of intracellular iron and most probably with regard to their labile iron pool. Yet, the relation between plasma ferritin and intracellular labile iron pool has not been fully clarified. Data from population studies document that the consumption of meat and lack of physical activity contribute to increased iron stores. Patients with hereditary hemochromatosis, despite extreme iron storage, do not show increased manifestation of atherosclerosis probably due to the low expression of hepcidin in macrophages.

scholarly journals Ferroptosis induction induced by ginkgetin enhances therapeutic  effect of cisplatin in EGFR wild type non-small cell lung cancer

2020 ◽  
Author(s):  
Jian-Shu Lou ◽  
Li-Ping Zhao ◽  
Zhi-Hui Huang ◽  
Xia-Yin Chen ◽  
Jing-Ting Xu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Lipid Peroxidation ◽  
Small Cell ◽  
Anticancer Effect ◽  
Small Cell Lung ◽  
Labile Iron Pool ◽  
Ros Formation ◽  
Labile Iron ◽  
Iron Pool

Abstract Background Cisplatin (DDP) is the first-in-class drug for advanced and non-targetable non-small cell lung cancer (NSCLC). Recent study indicates that DDP could slightly induce non apoptotic cell death ferroptosis, and the cytotoxicity was promoted by ferroptosis inducer. The agents enhancing ferroptosis level therefore may increase anticancer effect of DDP. Several lines of evidence support the usage of phytochemicals in therapy of NSCLC. Ginkgetin, a bioflavonoid derived from Ginkgo biloba leaves, showed anti-cancer effect on NSCLC both in vitro and in vivo, which could strongly trigger autophagy. Ferroptosis can be triggered by autophagy, and which regulates redox homeostasis. Thus, we aim to elucidate the possible role of ferroptosis induction in accounting for synergy of ginkgetin with DDP in cancer therapy.Methods Ginkgetin promoted DDP-induced anticancer effect was observed via cytotoxicity assay and western blot. Ferroptosis triggered by ginkgetin in DDP treated NSCLC was observed via lipid peroxidation assay, labile iron pool assay, western blot, and QPCR. With ferroptosis blocking, the contribution of ferroptosis on ginkgetin + DDP induced cytotoxicity, Nrf2/HO-1 axis and apoptosis were determined via luciferase assay, immunostaining, chromatin immunoprecipitation (CHIP), and flow cytometry. The role of ferroptosis in ginkgetin + DDP treated NSCLC cells was illustrated by the application of ferroptosis inhibitor, which was further demonstrated in xenograft nude mice model.Results Ginkgetin synergized cisplatin in cytotoxicity in NSCLC cells, which concomitant with increased labile iron pool and lipid peroxidation: both these processes were the key characteristics of ferroptosis. The induction of ferroptosis, mediated by ginkgetin, was further confirmed by decline expressions of SLC7A11, GPX4 and GSH/GSSG ratio. In parallel, ginkgetin disrupted redox hemeostasis in DDP-treated cells, demonstrated by the enhanced ROS formation and inactivation on Nrf2/HO-1 axis. Ginkgetin also enhanced DDP-induced mitochondrial membrane potential (MMP) loss and apoptosis in cultured NSCLC cells. Furthermore, blocking ferroptosis reversed the gingketin-induced inactivation on Nrf2/HO-1, as well as the elevation on ROS formation, MMP loss and apoptosis in DDP-treated NSCLC cells.Conclusion This study firstly reported that ginkgetin promoted DDP-induced anticancer effect, which could be accounted by induction of ferroptosis.

The Cellular Labile Iron Pool and Intracellular Ferritin in K562 Cells

Blood ◽  
1999 ◽  
Vol 94 (6) ◽  
pp. 2128-2134 ◽  
Author(s):  
Abraham M. Konijn ◽  
Hava Glickstein ◽  
Boris Vaisman ◽  
Esther G. Meyron-Holtz ◽  
Itzchak N. Slotki ◽  
...  
Keyword(s):  
Biological Effects ◽  
Ferritin Level ◽  
Regulatory Protein ◽  
Iron Chelation ◽  
K562 Cells ◽  
Iron Chelator ◽  
Labile Iron Pool ◽  
Cellular Iron ◽  
Labile Iron ◽  
Iron Pool

The labile iron pool (LIP) harbors the metabolically active and regulatory forms of cellular iron. We assessed the role of intracellular ferritin in the maintenance of intracellular LIP levels. Treating K562 cells with the permeant chelator isonicotinoyl salicylaldehyde hydrazone reduced the LIP from 0.8 to 0.2 μmol/L, as monitored by the metalo-sensing probe calcein. When cells were reincubated in serum-free and chelator-free medium, the LIP partially recovered in a complex pattern. The first component of the LIP to reappear was relatively small and occurred within 1 hour, whereas the second was larger and relatively slow to occur, paralleling the decline in intracellular ferritin level (t½= 8 hours). Protease inhibitors such as leupeptin suppressed both the changes in ferritin levels and cellular LIP recovery after chelation. The changes in the LIP were also inversely reflected in the activity of iron regulatory protein (IRP). The 2 ferritin subunits, H and L, behaved qualitatively similarly in response to long-term treatments with the iron chelator deferoxamine, although L-ferritin declined more rapidly, resulting in a 4-fold higher H/L-ferritin ratio. The decline in L-ferritin, but not H-ferritin, was partially attenuated by the lysosomotrophic agent, chloroquine; on the other hand, antiproteases inhibited the degradation of both subunits to the same extent. These findings indicate that, after acute LIP depletion with fast-acting chelators, iron can be mobilized into the LIP from intracellular sources. The underlying mechanisms can be kinetically analyzed into components associated with fast release from accessible cellular sources and slow release from cytosolic ferritin via proteolysis. Because these iron forms are known to be redox-active, our studies are important for understanding the biological effects of cellular iron chelation.

scholarly journals Role of Ferritin in the Control of the Labile Iron Pool in Murine Erythroleukemia Cells

1998 ◽  
Vol 273 (25) ◽  
pp. 15382-15386 ◽  
Author(s):  
Virginie Picard ◽  
Silvina Epsztejn ◽  
Paolo Santambrogio ◽  
Z. Ioav Cabantchik ◽  
Carole Beaumont
Keyword(s):  
Labile Iron Pool ◽  
Erythroleukemia Cells ◽  
Labile Iron ◽  
Iron Pool ◽  
Murine Erythroleukemia ◽  
Murine Erythroleukemia Cells

Repression of ferritin expression modulates cell responsiveness to H-ras-induced growth

2002 ◽  
Vol 30 (4) ◽  
pp. 777-780 ◽  
Author(s):  
O. Kakhlon ◽  
Y. Gruenbaum ◽  
Z. I. Cabantchik
Keyword(s):  
Cell Proliferation ◽  
Growth Retardation ◽  
Dominant Negative ◽  
Ras Oncogene ◽  
Hek 293 ◽  
Labile Iron Pool ◽  
293 Cells ◽  
Labile Iron ◽  
Iron Pool

We assessed the role of the cell labile iron pool in mediating oncogene-induced cell proliferation via repression of ferritin expression. When HEK-293 cells, engineered to inducibly express either active (+) or dominant-negative (-) forms of the H-ras oncogene, were treated with antisense nucleotides to ferritin subunits they displayed (a) decreased ferritin levels, (b) increased labile iron pool and either (c) faster growth in cells induced to express H-Ras (+) or (d) recovery from growth retardation in dominant-negative H-Ras-induced cells. Our studies support the view that the role of down-modulation of ferritin expression by some oncogene-evoked proliferation proceeds via expansion of the cellular labile iron pool.

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