Activation of Transferrin Receptor 1 by c-Myc Enhances Cellular Proliferation and Tumorigenesis

Program in Human Genetics and Molecular Biology, The Johns Hopkins School of Medicine, Baltimore, MD 21205, USA.
Molecular and Cellular Biology (Impact Factor: 4.78). 04/2006; 26(6):2373-86. DOI: 10.1128/MCB.26.6.2373-2386.2006
Source: PubMed


Overexpression of transferrin receptor 1 (TFRC1), a major mediator of iron uptake in mammalian cells, is a common feature of human malignancies. Therapeutic strategies designed to interfere with tumor iron metabolism have targeted TFRC1. The c-Myc oncogenic transcription factor stimulates proliferation and growth by activating thousands of target genes. Here we demonstrate that TFRC1 is a critical downstream target of c-Myc. Using in vitro and in vivo models of B-cell lymphoma, we show that TFRC1 expression is activated by c-Myc. Chromatin immunoprecipitation experiments reveal that c-Myc directly binds a conserved region of TFRC1. In light of these findings, we sought to determine whether TFRC1 is required for c-Myc-mediated cellular proliferation and cell size control. TFRC1 inhibition decreases cellular proliferation and results in G1 arrest without affecting cell size. Consistent with these findings, expression profiling reveals that TFRC1 depletion alters expression of genes that regulate the cell cycle. Furthermore, enforced TFRC1 expression confers a growth advantage to cells and significantly enhances the rate of c-Myc-mediated tumor formation in vivo. These findings provide a molecular basis for increased TFRC1 expression in human tumors, illuminate the role of TFRC1 in the c-Myc target gene network, and support strategies that target TFRC1 for cancer therapy.

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Available from: Chi V Dang, Jan 20, 2014
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    • "Accumulating evidence suggests that the Myc family is an excellent target for anti-cancer therapeutics due to its involvement in cell growth, metabolism, proliferation, apoptosis, and differentiation. Numerous c-Myc targeting strategies, including the inhibition of c-Myc expression or the interruption c-Myc and its downstream effects, are currently being used in experimental therapeutics for several types of cancer [5,18]. Most of these approaches continue to be hampered by technical difficulties pertaining largely to delivery and the fact that many c-Myc target genes are functionally redundant and/or cell type specific [19]. "
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    ABSTRACT: Epithelial ovarian carcinoma is the most lethal gynecological cancer due to its silent onset and recurrence with resistance to chemotherapy. Overexpression of oncogene c-Myc is one of the most frequently encountered events present in ovarian carcinoma. Disrupting the function of c-Myc and its downstream target genes is a promising strategy for cancer therapy. Our objective was to evaluate the potential effects of small-molecule c-Myc inhibitor, 10058-F4, on ovarian carcinoma cells and the underlying mechanisms by which 10058-F4 exerts its actions. Using MTT assay, colony formation, flow cytometry and Annexin V FITC assays, we found that 10058-F4 significantly inhibited cell proliferation of both SKOV3 and Hey ovarian cancer cells in a dose dependent manner through induction of apoptosis and cell cycle G1 arrest. Treatment with 10058-F4 reduced cellular ATP production and ROS levels in SKOV3 and Hey cells. Consistently, primary cultures of ovarian cancer treated with 10058-F4 showed induction of caspase-3 activity and inhibition of cell proliferation in 15 of 18 cases. The response to 10058-F4 was independent the level of c-Myc protein over-expression in primary cultures of ovarian carcinoma. These novel findings suggest that the growth of ovarian cancer cells is dependent upon c-MYC activity and that targeting c-Myc-Max heterodimerization could be a potential therapeutic strategy for ovarian cancer.
    Journal of Translational Medicine 08/2014; 12(1):226. DOI:10.1186/s12967-014-0226-x · 3.93 Impact Factor
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    • "TFRC, transferrin receptor, is known to be expressed in many tumor types (Table S3). Expression of VEGFA and TFRC is commonly regulated by HIF and MYC, which promote angiogenesis and proliferation, respectively [58]–[60]. The connection between these two TFs via their target genes is known to confer a metabolic advantage to tumors under hypoxia, which is a common condition in malignant diseases [61], [62]. "
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    ABSTRACT: A universal cancer biomarker candidate for diagnosis is supposed to distinguish, within a broad range of tumors, between healthy and diseased patients. Recently published studies have explored the universal usefulness of some biomarkers in human tumors. In this study, we present an integrative approach to search for potential common cancer biomarkers. Using the TFactS web-tool with a catalogue of experimentally established gene regulations, we could predict transcription factors (TFs) regulated in 305 different human cancer cell lines covering a large panel of tumor types. We also identified chromosomal regions having significant copy number variation (CNV) in these cell lines. Within the scope of TFactS catalogue, 88 TFs whose activity status were explained by their gene expressions and CNVs were identified. Their minimal connected network (MCN) of protein-protein interactions forms a significant module within the human curated TF proteome. Functional analysis of the proteins included in this MCN revealed enrichment in cancer pathways as well as inflammation. The ten most central proteins in MCN are TFs that trans-regulate 157 known genes encoding secreted and transmembrane proteins. In publicly available collections of gene expression data from 8,525 patient tissues, 86 genes were differentially regulated in cancer compared to inflammatory diseases and controls. From TCGA cancer gene expression data sets, 50 genes were significantly associated to patient survival in at least one tumor type. Enrichment analysis shows that these genes mechanistically interact in common cancer pathways. Among these cancer biomarker candidates, TFRC, MET and VEGFA are commonly amplified genes in tumors and their encoded proteins stained positive in more than 80% of malignancies from public databases. They are linked to angiogenesis and hypoxia, which are common in cancer. They could be interesting for further investigations in cancer diagnostic strategies.
    PLoS ONE 06/2012; 7(6):e39666. DOI:10.1371/journal.pone.0039666 · 3.23 Impact Factor
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    • "Increased AKT activity can increase TFRC cell surface expression, leading to increased TFRC activation [27]. TFRC has recently been reported to be a direct transcriptional target of MYC, and TFRC was shown to be required for MYC-mediated cell proliferation [28], providing a direct mechanism by which AKT can mediate TFRC cell surface expression. TFRC RNA levels were decreased in response to treatment in the SKOV-3 xenograft, and in BT474, SKOV-3, and LNCaP cell culture experiments (Additional file 9 Figure S4). "
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    ABSTRACT: Inappropriate activation of AKT signaling is a relatively common occurrence in human tumors, and can be caused by activation of components of, or by loss or decreased activity of inhibitors of, this signaling pathway. A novel, pan AKT kinase inhibitor, GSK690693, was developed in order to interfere with the inappropriate AKT signaling seen in these human malignancies. Causal network modeling is a systematic computational analysis that identifies upstream changes in gene regulation that can serve as explanations for observed changes in gene expression. In this study, causal network modeling is employed to elucidate mechanisms of action of GSK690693 that contribute to its observed biological effects. The mechanism of action of GSK690693 was evaluated in multiple human tumor cell lines from different tissues in 2-D cultures and xenografts using RNA expression and phosphoproteomics data. Understanding the molecular mechanism of action of novel targeted agents can enhance our understanding of various biological processes regulated by the intended target and facilitate their clinical development. Causal network modeling on transcriptomic and proteomic data identified molecular networks that are comprised of activated or inhibited mechanisms that could explain observed changes in the sensitive cell lines treated with GSK690693. Four networks common to all cell lines and xenografts tested were identified linking GSK690693 inhibition of AKT kinase activity to decreased proliferation. These networks included increased RB1 activity, decreased MYC activity, decreased TFRC activity, and increased FOXO1/FOXO3 activity. AKT is involved in regulating both cell proliferation and apoptotic pathways; however, the primary effect with GSK690693 appears to be anti-proliferative in the cell lines and xenografts evaluated. Furthermore, these results indicate that anti-proliferative responses to GSK690693 in either 2-D culture or xenograft models may share common mechanisms within and across sensitive cell lines.
    BMC Genomics 07/2010; 11(1):419. DOI:10.1186/1471-2164-11-419 · 3.99 Impact Factor
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