Iron Chelators Inhibit the Growth and Induce the Apoptosis of Kaposi's Sarcoma Cells and of their Putative Endothelial Precursors

Simonart, Thierry; Heenen, Michel; Degraef, Chantal; Andrei, Gracíela; Mosselmans, Roger; Hermans, Philippe; Vooren, Jean‐Paul Van; Noël, Jean‐Christophe; Boelaert, Johan R.; Snoeck, Robert

doi:10.1046/j.1523-1747.2000.00119.x

Cited by 86 publications

(71 citation statements)

References 36 publications

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“…In F-36P cells, IL-3 induced cyclin D1 expression was shown to be inhibited by dominant negative-STAT5, while constitutively activated-STAT5 induced IL-3 independent cyclin D1 promoter activity (Simonart et al, 2000). Indeed, the cyclin D1 promoter was shown to contain binding sites for STAT3 and -5 (Bromberg et al, 1999;Matsumura et al, 1999;de Groot et al, 2000).…”

Section: Discussionmentioning

confidence: 97%

“…DFO, that mimics hypoxia and a similar oxygen sensor in the hypoxia regulation, induces a hypoxic condition (Tazuke et al, 1998;Park et al, 2000;Park et al, 2001a). The effect of DFO on DNA synthesis and repair was reflected in studies that have shown that treatment with DFO induces apoptosis in rapidly growing tumor cells (Fukuchi et al, 1994;Simonart et al, 2000). This new finding indicates that there is another pathway that is different from the HIF-1 signaling pathway, which is known as a major mechanism in hypoxia signaling.…”

Section: Introductionmentioning

confidence: 96%

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Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

Joung

Lim²,

Lee³

et al. 2005

Exp Mol Med

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Hypoxia, a common consequence of solid tumor growth in breast cancer or other cancers, serves to propagate a cascade of molecular pathways which include angiogenesis, glycolysis, and various cellcycle control proteins. As we have shown previously, hypoxia activates STAT5 (signal transducer and activator of transcription 5) and increases its binding activity to the GAS element in mammary epithelial cells. In this study we attempted to elucidate the mechanism by which cyclin D1 is regulated by the STAT5 protein under hypoxic conditions. Our data demonstrate that hypoxia (2% O 2 ) or desferrioxamine (DFO) induces tyrosine and serine phosphorylation of STAT5 in human breast cancer cells (MCF-7) and mammary epithelial cells (HC11). Imunoprecipitation and subsequent Western analysis showed that Jak2 leads to the tyrosine phosphorylation and activation of STAT5a or STAT5b under hypoxic conditions. Using a transfected COS-7 cell model system, we demonstrate that the activity of a cyclin D1 promoter-luciferase construct increased under hypoxic conditions or DFO treatment. The activity of the STAT5b/cyclin D1 promoter increased significantly by 12 h of hypoxia, whereas the activity of the STAT5a/cyclin D1 promoter was unaffected under hypoxic conditions. These increases in promoter activity are predominantly mediated by the Jak2/ STAT5b signaling pathway. We have shown by EMSA that hypoxia induces STAT5 to bind to the cyclin D1 promoter (GAS-1) in MCF-7 and HC11 cells. These data suggest that STAT5b may mediate the transcriptional activation of cyclin D1 after hypoxic stimulation.

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 96%

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

Joung

Lim²,

Lee³

et al. 2005

Exp Mol Med

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“…4). Chelators have also been shown to inhibit the growth and induce apoptosis in Kaposi sarcoma cells, but ROS or transcription factors were not measured [38].…”

Section: Discussionmentioning

confidence: 99%

Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes

Meyskens¹,

McNulty²,

Buckmeier³

et al. 2001

Free Radical Biology and Medicine

114

100

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Abstract-Melanocytes and melanoma cells contain melanin, a complex polymer that modulates redox changes in these cells. Relative intracellular hydrogen peroxide levels measured by dichlorodihydrofluorescein are similar in the two cell types, but the levels of superoxide anion measured by dihydroethidium were markedly increased in melanoma cells. Chelator-induced oxidative stress is efficiently suppressed by melanocytes without substantial recruitment of the transcription factors NF-B and AP-1 as measured by electrophoretic mobility shift assay and quantitated by densitometry or by a change in frequency of apoptosis as determined by annexin V binding. In contrast, NF-B in melanoma cells is strongly recruited by changes in redox status and exhibits a correlative relationship to intracellular hydrogen peroxide (but not superoxide anion). However, the response of the NF-B pathway to intracellular hydrogen peroxide is anomalous, including downregulation of p65 and IB␣ RNA expression (Northern blot). Additionally, recruitment of AP-1 binding in melanoma cells was directly correlated with intracellular levels of superoxide anion (but not hydrogen peroxide). Neither the degree of NF-B nor AP-1 binding in melanoma cells was related to the frequency of apoptosis. The responsiveness of NF-B and AP-1 recruitment to intracellular levels of hydrogen peroxide and superoxide anion without concomitant control of apoptosis provides a general mechanism by which these cells can escape noxious injury (e.g., chemotherapy). The marked enhancement of apoptosis in melanoma cells by chelators indicates, however, that this alteration can be circumvented and offers a unique therapeutic window to explore.

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“…DFO mainly arrests cells at the G 1 /S (15)(16)(17) phase of the cycle and has been shown to induce apoptosis in multiple cell types (16,18). Inhibition of cell cycle progression is also reflected by the effect of DFO on cell cycle-related molecules, particularly decreasing the protein levels of cyclin D1 and to lesser extent, cyclin A and B1 (19,20).…”

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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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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Iron Chelators Inhibit the Growth and Induce the Apoptosis of Kaposi's Sarcoma Cells and of their Putative Endothelial Precursors

Cited by 86 publications

References 36 publications

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

Hypoxia activates the cyclin D1 promoter via the Jak2/STAT5b pathway in breast cancer cells

Aberrant redox regulation in human metastatic melanoma cells compared to normal melanocytes

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

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