The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

Rao, V. Ashutosh; Klein, Sarah R.; Agama, Keli; Toyoda, Eiji; Adachi, Noritaka; Pommier, ﻿Yves; Shacter, Emily

doi:10.1158/0008-5472.can-08-1437

Cited by 138 publications

(142 citation statements)

References 45 publications

(68 reference statements)

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“…It is important to note that the redox-inert DFO-iron complex possesses no anti-proliferative activity, whereas the Dp44mT-iron complexes exert anti-proliferative activity that is similar to that of Dp44mT alone (27). Hence, the anti-proliferative activity of the chelator-iron complexes or the chelator itself can be correlated with their ability to induce JNK and p38 phosphorylation that is known to have anti-proliferative and pro-apoptotic roles (23,25).…”

Section: Resultsmentioning

confidence: 99%

“…Tumor xenografts taken from Dp44mT-treated mice demonstrated increased apoptosis and up-regulation of the tumor growth and metastasis suppressor, N-myc downstream-regulated gene-1 (Ndrg1) (13,14). Recently, Dp44mT was also shown to selectively inhibit topoisomerase II␣ (23). Furthermore, unlike DFO, the iron com-plexes of Dp44mT can cause reactive oxygen species (ROS) generation, which may mediate cytotoxicity (13).…”

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confidence: 99%

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

Yu¹,

Richardson

2011

Journal of Biological Chemistry

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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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Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

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

Yu¹,

Richardson

2011

Journal of Biological Chemistry

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“…Several studies have demonstrated that the mechanism of the anti-tumor action of iron chelators is linked to the inhibition of DNA synthesis, the induction of DNA damage, G 1 -S phase cell cycle arrest, and the activation of apoptosis (15,17); however, research on targeting iron metabolism in cancer cells for anti-tumor therapy is still in its infancy (15).…”

Section: Modulation Of Intracellular Iron Metabolism By Iron Chelatiomentioning

confidence: 99%

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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“…Many cancers exhibit an increased requirement for iron, presumably because of the need for iron as a cofactor in proteins essential to sustain growth and proliferation (1–3). Modulation of iron-regulatory proteins affects growth of lung tumor xenografts (4, 5), and agents that deplete iron are currently under investigation as anticancer therapies (6–9). …”

Section: Introductionmentioning

confidence: 99%

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

Pinnix¹,

Miller²,

Wang³

et al. 2010

Science Translational Medicine

245

278

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Ferroportin and hepcidin are critical proteins for the regulation of systemic iron homeostasis. Ferroportin is the only known mechanism for export of intracellular non–heme-associated iron; its stability is regulated by the hormone hepcidin. Although ferroportin profoundly affects concentrations of intracellular iron in tissues important for systemic iron absorption and trafficking, ferroportin concentrations in breast cancer and their influence on growth and prognosis have not been examined. We demonstrate here that both ferroportin and hepcidin are expressed in cultured human breast epithelial cells and that hepcidin regulates ferroportin in these cells. Further, ferroportin protein is substantially reduced in breast cancer cells compared to nonmalignant breast epithelial cells; ferroportin protein abundance correlates with metabolically available iron. Ferroportin protein is also present in normal human mammary tissue and markedly decreased in breast cancer tissue, with the highest degree of anaplasia associated with lowest ferroportin expression. Transfection of breast cancer cells with ferroportin significantly reduces their growth after orthotopic implantation in the mouse mammary fat pad. Gene expression profiles in breast cancers from >800 women reveal that decreased ferroportin gene expression is associated with a significant reduction in metastasis-free and disease-specific survival that is independent of other breast cancer risk factors. High ferroportin and low hepcidin gene expression identifies an extremely favorable cohort of breast cancer patients who have a 10-year survival of >90%. Ferroportin is a pivotal protein in breast biology and a strong and independent predictor of prognosis in breast cancer.

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The Iron Chelator Dp44mT Causes DNA Damage and Selective Inhibition of Topoisomerase IIα in Breast Cancer Cells

Cited by 138 publications

References 45 publications

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

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

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

Ferroportin and Iron Regulation in Breast Cancer Progression and Prognosis

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