The role of iron in cell cycle progression and the proliferation of neoplastic cells

Le, Nghia T.V.

doi:10.1016/s0304-419x(02)00068-9

Cited by 301 publications

(349 citation statements)

References 145 publications

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“…Insufficient concentrations of iron and copper can therefore impede cellular functions. Indeed cells starved of iron are unable to progress from the G1 phase to the S phase in the cell cycle process [47]. The transcriptomic analysis also showed that 56MESS suppressed the biosynthesis of sulfur-containing amino acids-methionine and cysteine.…”

Section: Discussionmentioning

confidence: 98%

“…Iron and copper are required by proliferating cancer cells during carcinogenesis [32,39,59,77] and high levels of iron and copper were found in certain tumour cells and tissues, including breast cancer cells [17,33]. As iron and copper metabolism is up-regulated in neoplastic tumours [29,39,41,44,47,59,62,65,72], 56MESS and other complexes in this class should be assessed, in combination with cisplatin, in the cancer models that have elevated iron and copper metabolism. Indeed chelating cellular copper has recently been shown to selectively enhance the therapeutic efficacy of cisplatin in a mouse model of human cervical cancer [34].…”

Section: Discussionmentioning

confidence: 99%

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Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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Platinum-based DNA metallointercalators are structurally different from the covalent DNA binders such as cisplatin and its derivatives but have potent in vitro activity in cancer cell lines. However, limited understanding of their molecular mechanisms of cytotoxic action greatly hinders their further development as anticancer agents. In this study, a lead platinum-based metallointercalator, [(5,6-dimethyl-1,10-phenanthroline) (1S,2S-diaminocyclohexane) platinum(II)] 2+ (56MESS) was found to be 163-fold more active than cisplatin in a cisplatin-resistant cancer cell line. By using transcriptomics in a eukaryotic model organism, yeast Saccharomyces cerevisiae, we identified 93 genes that changed their expressions significantly upon exposure of 56MESS in comparison to untreated controls (p≤0.05). Bioinformatic analysis of these genes demonstrated that iron and copper metabolism, sulfur-containing amino acids and stress response were involved in the cytotoxicity of 56MESS. Follow-up experiments showed that the iron and copper concentrations were much lower in 56MESS-treated cells compared to controls as measured by inductively coupled plasma optical emission spectrometry. Deletion mutants of the key genes in the iron and copper metabolism pathway and glutathione synthesis were sensitive to 56MESS. Taken together, the study demonstrated that the cytotoxic action of 56MESS is mediated by its ability to disrupt iron and copper metabolism, suppress the biosynthesis of sulfur-containing amino acids and attenuate cellular defence capacity. As these mechanisms are in clear contrast to the DNA binding mechanism for cisplatin and its derivative, 56MESS may be able to overcome cisplatinresistant cancers. These findings have provided basis to further develop the platinum-based metallointercalators as anticancer agents.

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Section: Discussionmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

et al. 2011

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“…1). Because As-8w-HOS cells exhibit malignant characteristics, such as growth in soft agar that is lacking in parental HOS cells, these results indicate that transformed HOS cells need more iron to continue their growth [24]. Based on these initial findings, we postulated that the increased iron levels in As-8w-HOS cells are accompanied by an increase in ferritin and a decrease in TfR, a normal mechanism controlling iron homeostasis.…”

Section: Discussionmentioning

confidence: 88%

“…Iron is easily cycled between two redox states, ferrous ions (Fe 2+ ) and ferric ions (Fe 3+ ), which provide electrons for enzymatic and free radical reactions [20,21]. Although iron deficiency can cause anemia leading to decreased oxygen transport [22], its excess can also cause damage leading to adverse health effects, such as inflammation and cancer [23][24][25][26][27][28][29][30][31][32]. The damage caused by excess iron is thought to be mediated by redox cycling between ferrous and ferric states, via Haber-Weiss, Fenton, or autoxidation reactions, producing powerful oxygen free radicals [33][34][35].…”

Section: Introductionmentioning

confidence: 99%

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Eckard

Chen

et al. 2006

Free Radical Biology and Medicine

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Chronic exposure to low doses of arsenite causes transformation of human osteogenic sarcoma (HOS) cells. Although oxidative stress is considered important in arsenite-induced cell transformation, the molecular and cellular mechanisms by which arsenite transforms human cells are still unknown. In the present study, we investigated whether altered iron homeostasis, known to affect cellular oxidative stress, can contribute to the arsenite-mediated cell transformation. Using arsenite-induced HOS cell transformation as a model, it was found that total iron levels are significantly higher in transformed HOS cells in comparison to parental control HOS cells. Under normal iron metabolism conditions, iron homeostasis is tightly controlled by inverse regulation of ferritin and transferrin receptor (TfR) through iron regulatory proteins (IRP). Increased iron levels in arsenite transformed cells should theoretically lead to higher ferritin and lower TfR in these cells than in controls. However, the results showed that both ferritin and TfR are decreased, apparently through two different mechanisms. A lower ferritin level in cytoplasm was due to the decreased mRNA in the arsenitetransformed HOS cells, while the decline in TfR was due to a lowered IRP-binding activity. By challenging cells with iron, it was further established that arsenite-transformed HOS cells are less responsive to iron treatment than control HOS cells, which allows accumulation of iron in the transformed cells, as exemplified by significantly lower ferritin induction. On the other hand, caffeic acid phenethyl ester (CAPE), an antioxidant previously shown to suppress As-mediated cell transformation, prevents As-mediated ferritin depletion. In conclusion, our results suggest that altered iron homeostasis contributes to arsenite-induced oxidative stress and, thus, may be involved in arsenite-mediated cell transformation.

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“…Myc and PIAS2 (Miz1) cooperate to activate or repress expression of Nramp1 (Bowen et al, 2002;Lapham et al, 2004). Although previous literature reports have not linked Mitf directly to the regulation of cellular iron homeostasis, Mitf has been shown to interact with PIAS3 (Levy et al, 2003;Sonnenblick et al, 2004), and to regulate expression of HIF-1α (Busca et al, 2005), a transcription factor that functions in oxygen sensing, and cellular adaptation to iron deficiency (Le and Richardson, 2002;Lee et al, 2006).…”

Section: (3) Ingenuity Pathway Analysismentioning

confidence: 99%

Altered expression of the iron transporter Nramp1 (Slc11a1) during fetal development of the retinal pigment epithelium in microphthalmia-associated transcription factor Mitfmi and Mitfvitiligo mouse mutants

Waes

Smith

Waes

et al. 2008

Experimental Eye Research

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Microphthalmia-associated Transcription Factor (Mitf) is expressed in neural crest cell-derived melanocytes, and in the retinal pigment epithelium (RPE) during ocular development. Mutations in Mitf are associated with auditory/visual/pigmentary syndromes in humans. Mitf mi/mi mouse mutants lack pigmentation, and are microphthalmic, while Mitf vit/vit mouse mutants display abnormal RPE pigmentation, and progressive retinal degeneration. Microarray analysis was used to identify novel downstream gene targets/pathways in the RPE that are altered by mutations in the transcription factor Mitf. Using the Affymetrix platform, gene expression profiles were generated using the eyes of E13.5 mouse fetuses that were wildtype, heterozygous, or homozygous for the Mitf mi mutation. In a separate experiment, eyes from E13.5 mouse fetuses homozygous for the Mitf vit mutation were compared to eyes from the C57BL/6 control background strain. Statistical analyses were performed using Robust Multiarray Average, mixed-effects ANOVA and random-variance t-tests. Altered expression of genes involved in pigment formation, melanosome biogenesis/transport, and redox homeostasis were observed. 12 genes were commonly mis-regulated in the eyes of both Mitf mutants: 10 of these genes were downregulated in both mutants relative to controls, while 2 of the genes (Nramp1 (Slc11a1) and epoxide hydrolase) were downregulated in Mitf mi/mi mutants, and conversely, upregulated in Mitf vit/vit mutants. Quantitative RT-PCR and immunohistochemistry were used to confirm altered gene/protein expression. RPE expression of the Fe +2 iron transporter Nramp1 (Slc11a1) has not previously been reported. Fe +2 is an important co-factor utilized by the iron-dependent isomerohydrolase RPE65 in the retinoid visual cycle. However, excess accumulation of Fe +2 in the RPE has recently been associated with oxidative damage and age-related macular degeneration. Abnormal pigmentation and increased activity of Slc11a1 in the RPE of Mitf vit mice may contribute to the pathology and progressive retinal degeneration observed in these mutants.

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The role of iron in cell cycle progression and the proliferation of neoplastic cells

Cited by 301 publications

References 145 publications

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Identification of the molecular mechanisms underlying the cytotoxic action of a potent platinum metallointercalator

Altered iron homeostasis involvement in arsenite-mediated cell transformation

Altered expression of the iron transporter Nramp1 (Slc11a1) during fetal development of the retinal pigment epithelium in microphthalmia-associated transcription factor Mitfmi and Mitfvitiligo mouse mutants

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