Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

So, Eui Young; Ausman, M; Sendo, Toshiaki; Ouchi, Toru

doi:10.1038/cddis.2011.9

Cited by 11 publications

(10 citation statements)

References 29 publications

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“…The present study showed that the dose-dependent increase in [Ca 2+ ]i was caused as a response to the addition of iron, both to K562 cells with and without DFO and the response was more sensitive in cells that were incubated with DFO against iron treatment. The treatment of various cancer cells with DFO has been shown in previous studies to induce apoptosis through the activation of various pro-apoptotic pathways [23][24][25][26][27]. Furthermore, the results of the present study demonstrate that the exposure of K562 cells to DFO induced a rise of [Ca 2+ ]i that was more sensitive to the iron concentration than K562 cells without DFO.…”

Section: Discussionsupporting

confidence: 69%

“…Characterizing such changes may help to identify new therapeutic targets [39,40]. It has been shown that DFO triggers apoptosis by the activation of various pro-apoptotic pathways [24][25][26][27]. Our results demonstrate that exposure of K562 a cell to DFO increases the sensitivity of iron as a calcium response and boosts the sensitivity to DOX.…”

Section: Discussionmentioning

confidence: 60%

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Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

Yalcintepe

Halis

2015

Bosn J of Basic Med Sci

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Increased intracellular iron levels can both promote cell proliferation and death, as such; iron has a "two-sided effect" in the delicate balance of human health. Though the role of iron in the development of cancer remains unclear, investigations of iron chelators as anti-tumor agents have revealed promising results. Here, we investigated the influence of iron and desferrioxamine (DFO), the iron chelating agent on intracellular calcium in a human leukemia cell line, K562. Iron uptake is associated with increased reactive oxygen species (ROS) generation. Therefore, we showed that iron also caused dose-dependent ROS generation in K562 cells. The measurement of intracellular calcium was determined using Furo-2 with a fluorescence spectrophotometer. The iron delivery process to the cytoplasmic iron pool was examined by monitoring the fluorescence of cells loaded with calcein-acetoxymethyl. Our data showed that iron increased intracellular calcium, and this response was 8 times higher when cells were incubated with DFO. K562 cells with DFO caused a 3.5 times increase of intracellular calcium in the presence of doxorubicin (DOX). In conclusion, DFO induces intracellular calcium and increases their sensitivity to DOX, a chemotherapeutic agent.

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Section: Discussionsupporting

confidence: 69%

Section: Discussionmentioning

confidence: 60%

Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

Yalcintepe

Halis

2015

Bosn J of Basic Med Sci

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“…Previous reports have shown that the treatment of various cancer cells with DFO induces apoptosis through the activation of various pro-apoptotic pathways (25)(26)(27)(28). Likewise, the results of the present study demonstrated that the exposure of MCF-7 and MDA-MB-231 human breast cancer cells to DFO induced the pro-apoptotic program; however, the underlying mechanisms of this activation differed in these cell lines.…”

Section: Mcf-7supporting

confidence: 68%

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Pogribny

Tryndyak

Pogribna

et al. 2013

International Journal of Oncology

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Abstract. Iron plays a vital role in the normal functioning of cells via the regulation of essential cellular metabolic reactions, including several DNA and histone-modifying proteins. The metabolic status of iron and the regulation of epige netic mechanisms are well-balanced and tightly controlled in normal cells; however, in cancer cells these processes are profoundly disturbed. Cancer-related abnormalities in iron metabolism have been corrected through the use of iron-chelating agents, which cause an inhibition of DNA synthesis, G 1 -S phase arrest, an inhibition of epithelial-to-mesenchymal transition, and the activation of apoptosis. In the present study, we show that, in addition to these well-studied molecular mechanisms, the treatment of wild-type TP53 MCF-7 and mutant TP53 MDA-MB-231 human breast cancer cells with desferrioxamine (DFO), a model iron chelator, causes significant epigenetic alterations at the global and gene-specific levels. Specifically, DFO treatment decreased the protein levels of the histone H3 lysine 9 demethylase, Jumonji domain-containing protein 2A (JMJD2A), in the MCF-7 and MDA-MB-231 cells and down-regulated the levels of the histone H3 lysine 4 demethylase, lysine-specific demethylase 1 (LSD1), in the MDA-MB-231 cells. These changes were accompanied by alterations in corresponding metabolically sensitive histone marks. Additionally, we demonstrate that DFO treatment activates apoptotic programs in MCF-7 and MDA-MB-231 cancer cells and enhances their sensitivity to the chemotherapeutic agents, doxorubicin and cisplatin; however, the mechanisms underlying this activation differ. The induction of apoptosis in wild-type TP53 MCF-7 cells was p53-dependent, triggered mainly by the down-regulation of the JMJD2A histone demethylase, while in mutant TP53 MDA-MB-231 cells, the activation of the p53-independent apoptotic program was driven predominantly by the epigenetic up-regulation of p21. IntroductionA growing body of evidence indicates the existence of an intimate link between the metabolic status and epigenetic regulation of cells (1,2). This is exemplified by the fact that a variety of small molecules involved in intercellular metabolism, including adenosine triphosphate, S-adenosylmethionine, nicotinamide adenine dinucleotide, flavin adenine dinucleotide, folate, acetyl coenzyme A, α-ketoglutarate and iron, are essential for the proper maintenance of the cellular epigenome.Iron is an essential trace element for normal cellular function. In addition to its significance in controlling a variety of cellular processes, including proliferation, DNA synthesis and repair, and mitochondrial electron transport, which are essential for the accurate maintenance of normal cellular homeostasis, iron plays a key regulatory role in the functioning of DNA and histone-modifying proteins (3,4). Specifically, the Jumonji domain-containing histone demethylase (JHDM) family, which catalyzes the demethylation of tri-and dimethylated lysine 9 and lysine 36 residues in histone H3 (5,6) and ten-eleven tra...

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“…It has been demonstrated that NCS treatment rapidly induces full activation of nuclear ATM. 16 , 17 Our results show that much stronger phosphorylation of ATM is observed at 6 h after NCS treatment, although SMC1 is phosphorylated as early as at 1 h ( Figure 1c ). Thus, cytoplasmic ATM could be differentially activated from the nuclear ATM.…”

Section: Resultsmentioning

confidence: 59%

Translational initiation regulated by ATM in dendritic cells development

Ouchi

2014

Cell Death Dis

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Ataxia telangiectasia mutated (ATM) protein has been implicated in multiple pathways such as DNA repair, cell cycle checkpoint, cell growth, development, and stem cell renewal. In this study, we demonstrate evidence that ATM is involved in granulocyte macrophage colony-stimulating factor (GM-CSF)-induced dendritic cell (DC) development from bone marrow (BM) cells. Inactivation of ATM protein results in decreased BM proliferation, leading to reduced DC development and their activity for T cell activation. Expression of Jak2, STAT5, and mTOR is suppressed in both wild-type and ATM-null BM prior to GM-CSF stimulation. Activation of those proteins is delayed and prolonged hypophosphorylation of 4EBP1 is observed in ATM-null BM when treated with GM-CSF, although Erk and p38 are similarly expressed and activated in both wild-type and ATM-null BM cell types. Akt is also suppressed in wild-type BM, and transduction of constitutively active Akt or STAT5 in ATM-null BM restores DC development. Together, these results illustrate that ATM deficiency causes impaired initiation of protein translation in BM, leading to immature development of DC.

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Phosphorylation of SMC1 by ATR is required for desferrioxamine (DFO)-induced apoptosis

Cited by 11 publications

References 29 publications

Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

Modulation of iron metabolism by iron chelation regulates intracellular calcium and increases sensitivity to doxorubicin

Modulation of intracellular iron metabolism by iron chelation affects chromatin remodeling proteins and corresponding epigenetic modifications in breast cancer cells and increases their sensitivity to chemotherapeutic agents

Translational initiation regulated by ATM in dendritic cells development

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