Iron overload and altered iron metabolism in ovarian cancer

Rockfield, Stephanie; Raffel, Joseph; Mehta, Rajil; Rehman, Nabila; Nanjundan, Meera

doi:10.1515/hsz-2016-0336

Cited by 36 publications

(31 citation statements)

References 134 publications

(184 reference statements)

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“…Since there is evidence that transition metals can promote DNA damage resulting in gene mutations 43 , we hypothesized that chronic iron exposure may be able to cause such mutations as well 44 . To address this question, we isolated genomic DNA from untreated and chronic FAC-treated FT194 cells for reverse transcriptase PCR using K-Ras specific primers, a common mutated gene in tumorigenesis, as previously described 30 .…”

Section: Resultsmentioning

confidence: 99%

Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer

2019

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Mechanisms underlying the pathogenesis of high-grade serous epithelial ovarian cancers (HGSOC) are not yet well defined although key precursor cells have been identified (including fimbriated fallopian tube epithelium, FTSECs). Since iron is elevated in endometriotic cysts and the pelvic cavity, it is suggested that this source of redox-active iron may contribute to ovarian cancer pathogenesis. Specifically, sources of nontransferrin-bound iron (NTBI) within the pelvic cavity could arise from ovulation, retrograde menstruation, follicular fluid, or iron overload conditions (i.e., hemochromatosis). Herein, we investigated the cellular response of p53-inactivated and telomerase-expressing (immortalized) FTSECs (Pax8 + /FoxJ1 − ) to NTBI (presented as ferric ammonium citrate (FAC), supplemented in media for >2 months) in order to assess its ability to promote the transition to a tumor-like phenotype; this cellular response was compared with immortalized FTSECs transformed with H-Ras V12A and c-Myc T58A . Both approaches resulted in increased cell numbers and expression of the oncogenic transcriptional regulator, ecotropic virus integration site 1 (EVI1, a gene most frequently amplified at 3q26.2 in HGSOC, represented by multiple variants), along with other oncogenic gene products. In contrast to the transformed cells, FAC-exposed FTSECs elicited elevated migratory capacity (and epithelial–mesenchymal transition mRNA profile) along with increased expression of DNA damage response proteins (i.e., FANCD2) and hTERT mRNA relative to controls. Interestingly, in FAC-exposed FTSECs, EVI1 siRNA attenuated hTERT mRNA expression, whereas siRNAs targeting β-catenin and BMI1 (both elevated with chronic iron exposure) reduced Myc and Cyclin D1 proteins. Collectively, our novel findings provide strong foundational evidence for potential iron-induced initiation events, including EVI1 alterations, in the pathogenesis of HGSOC, warranting further in depth investigations. Thus, these findings will substantially advance our understanding of the contribution of iron enriched within the pelvic cavity, which may identify patients at risk of developing this deadly disease.

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Section: Resultsmentioning

confidence: 99%

Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer

2019

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“…Specific mechanisms, such as iron absorption, iron recycling, and iron mobilization, are in place to regulate iron content at both a cellular and systemic level [1]; for comprehensive reviews, see [2,9]. Briefly, uptake of iron, either as transferrin-bound iron (TBI, holo-transferrin bound Fe(III)) or as non-transferrin bound iron (NTBI, Fe(II)), is mediated, respectively, via the transferrin receptor (CD71) and by solute carrier family 39 member 8 (SLC39A8/ZIP8) or solute carrier family 39 member 14 (SLC39A14/ZIP14) [10,11,12].…”

Section: Introductionmentioning

confidence: 99%

“…After TBI is endocytosed, Fe(III) is released from transferrin and then reduced to Fe(II) by the ferrireductase STEAP3 (six-transmembrane epithelial antigen of prostate 3) [14] prior to its release from the endosome via the DMT1 channel. Cytosolic iron may then (a) remain available for use in the LIP, (b) be transported to mitochondria to generate iron-sulfur (Fe-S) clusters, or (c) be stored within the ferritin complex (a process mediated by poly(RC) binding protein 1 (PCBP1)) [9,15]. Iron is released from the ferritin complex via the action of nuclear receptor coactivator 4 (NCOA4), which is involved in autophagy-mediated degradation of these iron complexes [16,17].…”

Section: Introductionmentioning

confidence: 99%

Links Between Iron and Lipids: Implications in Some Major Human Diseases

et al. 2018

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Maintenance of iron homeostasis is critical to cellular health as both its excess and insufficiency are detrimental. Likewise, lipids, which are essential components of cellular membranes and signaling mediators, must also be tightly regulated to hinder disease progression. Recent research, using a myriad of model organisms, as well as data from clinical studies, has revealed links between these two metabolic pathways, but the mechanisms behind these interactions and the role these have in the progression of human diseases remains unclear. In this review, we summarize literature describing cross-talk between iron and lipid pathways, including alterations in cholesterol, sphingolipid, and lipid droplet metabolism in response to changes in iron levels. We discuss human diseases correlating with both iron and lipid alterations, including neurodegenerative disorders, and the available evidence regarding the potential mechanisms underlying how iron may promote disease pathogenesis. Finally, we review research regarding iron reduction techniques and their therapeutic potential in treating patients with these debilitating conditions. We propose that iron-mediated alterations in lipid metabolic pathways are involved in the progression of these diseases, but further research is direly needed to elucidate the mechanisms involved.

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“…Iron is an essential element for many processes carried out within the cell. Abnormal iron regulation due to iron overload is destructive [72]. A large majority of iron (i.e., 3-5 g) in humans is contained in hemoglobin and the remainder is stored in protein complex ferritin in hepatocytes and macrophages [73].…”

Section: Blood/cycle-associated Factorsmentioning

confidence: 99%

Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review

et al. 2020

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This review focuses on pathogenesis of endometriosis, its possible biomarkers and role in endometriosis-associated ovarian cancer. We analyzed various databases to obtain new insights, theories, and biomarkers associated with endometriosis. There are several theories of endometriosis development and biomarker changes including atypical forms. A number of studies have attempted to establish specific, reliable biomarkers to help diagnose endometriosis and endometriosis-associated diseases on the basis of different pathogenetic pathways. Nevertheless, despite intensive research extending even to the molecular level, the origin, natural history, malignant transformation, and laboratory management of endometriosis and related diseases are not yet clearly defined. Therefore, early laboratory diagnoses of endometriosis, its atypical form, and Digital Features To view digital features for this article go to

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Iron overload and altered iron metabolism in ovarian cancer

Cited by 36 publications

References 134 publications

Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer

Chronic iron exposure and c-Myc/H-ras-mediated transformation in fallopian tube cells alter the expression of EVI1, amplified at 3q26.2 in ovarian cancer

Links Between Iron and Lipids: Implications in Some Major Human Diseases

Malignant Transformation and Associated Biomarkers of Ovarian Endometriosis: A Narrative Review

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