Ferritin Contributes to Melanoma Progression by Modulating Cell Growth and Sensitivity to Oxidative Stress

Baldi, Alfonso; Lombardi, Doug; Russo, Patrizia; Palescandolo, Emanuele; Luca, Antonio De; Santini, Daniele; Baldi, Feliciano; Rossiello, Luigi; Dell’Anna, Maria Lucia; Mastrofrancesco, Arianna; Maresca, Vittoria; Flori, Enrica; Natali, Pier Giorgio; Picardo, Mauro; Paggi, Marco G.

doi:10.1158/1078-0432.ccr-04-0631

Cited by 64 publications

(57 citation statements)

References 64 publications

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“…Second, it has been suggested that a decreased level of intracellular iron may increase angiogenesis and tumor progression via HIF-1a-induced up-regulation of VEGF [9]. Additionally, increased expression of ferritin in cancer cells has been associated with acquisition of metastatic and multidrug-resistant phenotype [31,32,34,37,38]. Indeed, the results of our study demonstrate the increased expression of VEGF ( Fig.…”

Section: Discussionsupporting

confidence: 53%

Role of ferritin alterations in human breast cancer cells

Shpyleva

Tryndyak

Kovalchuk

et al. 2010

Breast Cancer Res Treat

171

153

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Breast cancer is the most common malignancy in women. Successful treatment of breast cancer relies on a better understanding of the molecular mechanisms involved in breast cancer initiation and progression. Recent studies have suggested a crucial role of perturbations in ferritin levels and tightly associated with this, the deregulation of intracellular iron homeostasis; however, the underlying molecular mechanisms for the cancer-linked ferritin alterations remain largely unknown and often with conflicting conclusions. Therefore, this study was undertaken to define the role of ferritin in breast cancer. We determined that human breast cancer cells with an epithelial phenotype, such as MCF-7, MDA-MB-361, T-47D, HCC70 and cells, expressed low levels of ferritin light chain, ferritin heavy chain, transferrin, transferring receptor, and iron-regulatory proteins 1 and 2. In contrast, expression of these proteins was substantially elevated in breast cancer cells with an aggressive mesenchymal phenotype, such as Hs-578T, BT-549, and especially MDA-MB-231 cells. The up-regulation of ferritin light chain and ferritin heavy chain in MDA-MB-231 cells was accompanied by alterations in the subcellular distribution of these proteins as characterized by an increased level of nuclear ferritin and a lower level of the cellular labile iron pool as compared to MCF-7 cells. We established that ferritin heavy chain is a target of miRNA miR-200b, suggesting that its up-regulation in MDA-MB-231 cells may be triggered by the low expression of miR-200b. Ectopic up-regulation of miR-200b by transfection of MDA-MB-231 cells with miR-200b substantially decreased the level of ferritin heavy chain. More importantly, miR-200b-induced down-regulation of ferritin was associated with an increased sensitivity of the MDA-MB-231 cells to the chemotherapeutic agent doxorubicin. These results suggest that perturbations in ferritin levels are associated with the progression of breast cancer toward a more advanced malignant phenotype.

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Section: Discussionsupporting

confidence: 53%

Role of ferritin alterations in human breast cancer cells

Shpyleva

Tryndyak

Kovalchuk

et al. 2010

Breast Cancer Res Treat

171

153

View full text Add to dashboard Cite

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“…Moreover, the latter become more susceptible to oxidative stress and liable to apoptosis [3]. In our study, FLC expression in syncytiotrophoblast and mesenchymal and endothelial cells was similar in induced in spontaneous pregnancy, which attests to retained protective properties of the placenta and the absence of ART (IVF or ICSI) effects.…”

Section: Resultssupporting

confidence: 70%

Markers of Transmembrane and Energy Exchange in Cells of Terminal Placental Villi in Spontaneous and Induced Pregnancy

et al. 2012

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“…Increased levels of the tumorpromoting molecules transferrin receptor protein 1 (TFRC) and ferritin light chain (FTL) indicate aberrant iron metabolism. Deregulation of the proto-oncogene hepatocyte growth factor receptor (MET) as well as FTL are known to contribute to metastasis (20,21). Targeted proteomics analyses confirmed upregulation of FTL in the high TL group (Fig.…”

Section: Reprogramming Of Distant Organ Functions May Be Associated Wmentioning

confidence: 93%

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

Muqaku

Eisinger

Meier

et al. 2017

Molecular & Cellular Proteomics

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Pathophysiologies of cancer-associated syndromes such as cachexia are poorly understood and no routine biomarkers have been established, yet. Using shotgun proteomics, known marker molecules including PMEL, CRP, SAA, and CSPG4 were found deregulated in patients with metastatic melanoma. Targeted analysis of 58 selected proteins with multiple reaction monitoring was applied for independent data verification. In three patients, two of which suffered from cachexia, a tissue damage signature was determined, consisting of nine proteins, PLTP, CD14, TIMP1, S10A8, S10A9, GP1BA, PTPRJ, CD44, and C4A, as well as increased levels of glycine and asparagine, and decreased levels of polyunsaturated phosphatidylcholine concentrations, as determined by targeted metabolomics. Remarkably, these molecules are known to be involved in key processes of cancer cachexia. Based on these results, we propose a model how metastatic melanoma may lead to reprogramming of organ functions via formation of platelet activating factors from long-chain polyunsaturated phosphatidylcholines under oxidative conditions and via systemic induction of intracellular calcium mobilization. Calcium mobilization in platelets was demonstrated to alter levels of several of these marker molecules. Additionally, platelets from melanoma patients proved to be in a rather exhausted state, and platelet-derived eicosanoids implicated in tumor growth were found massively increased in blood from three melanoma patients. Platelets were thus identified Serum is the most important diagnostic sample type because of its minimal invasive access, a relatively high stability and its comprehensive representation of the physiological state of an individual. The latest technological development of mass spectrometric instruments, such as high resolution orbitrap instruments, improved substantially the quality and reliability of serum proteomics data (1). Shotgun proteomics analysis using the orbitrap technology is mainly applied for protein screening purposes (2). This method allows performing untargeted analyses, applicable for hypothesis-generating clinical applications. Targeted proteomics using triple-quadrupole mass spectrometric instruments, represents a complementary approach which is applied for protein quantification, hypotheses verification and validation (3). Enormous efforts have been invested in the last decades focusing on serum biomarker discovery (4). However, mass spectrometrybased proteomics analyses hardly managed to cope with biological variation. As a consequence, almost no clinically validated biomarker has emerged from these investigations yet, and a lot of questions about pathophysiological mechanisms remain unanswered.Using mass spectrometry-based proteomics, we have previously investigated melanoma and neighboring stroma cells, focusing on the identification of biomarkers associated with intrinsic and extrinsic drug resistance (5). In the present article, we followed the question how metastatic melanoma may reprogram distant organ functions, and how these...

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Ferritin Contributes to Melanoma Progression by Modulating Cell Growth and Sensitivity to Oxidative Stress

Cited by 64 publications

References 64 publications

Role of ferritin alterations in human breast cancer cells

Role of ferritin alterations in human breast cancer cells

Markers of Transmembrane and Energy Exchange in Cells of Terminal Placental Villi in Spontaneous and Induced Pregnancy

Multi-omics Analysis of Serum Samples Demonstrates Reprogramming of Organ Functions Via Systemic Calcium Mobilization and Platelet Activation in Metastatic Melanoma

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