Elemental iron is essential for cellular growth and homeostasis but it is potentially toxic to cells and tissues. Excess iron can contribute to tumour initiation and tumour growth.
Epidemiological evidence links increased body iron stores to increased cancer risk. High intake of dietary iron is associated with an increased risk for some cancers, particularly colorectal cancer. Hereditary haemochromatosis, a genetic disease that leads to excess iron accumulation, is associated with increased cancer risk.
Many types of cancer cells reprogramme iron metabolism in ways that result in net iron influx. They upregulate proteins that are involved in iron uptake, such as transferrin receptor 1 (TFR1), STEAP proteins and lipocalin 2 (LCN2), and decrease the expression of iron efflux proteins, such as ferroportin. Other iron-regulatory proteins, such as IRP1 and IRP2, contribute to cancer in ways that are less well understood.
Iron is crucial to many fundamental cellular processes, including DNA synthesis, proliferation, cell cycle regulation and the function of proteins containing iron–sulphur clusters. Iron–sulphur cluster-containing proteins include enzymes that contribute to maintaining genomic stability, as well as respiratory function.
Iron regulates crucial signalling pathways in tumours, including the hypoxia-inducible factor (HIF) and WNT pathways.
Measuring the expression of genes encoding proteins involved in iron metabolism may be useful in cancer prognosis. The expression of ferroportin, hepcidin, TFR1, haemochromatosis (HFE) and other genes involved in iron metabolism is linked to the prognosis of patients with breast cancer.
Iron is a target for cancer therapy. Iron chelators, TFR1 antibodies and cytotoxic ligands conjugated to transferrin (TF) represent some ways in which iron is being exploited therapeutically.
Iron is an essential nutrient that facilitates cell proliferation and growth. However, iron also has the capacity to engage in redox cycling and free radical formation. Therefore, iron can contribute to both tumour initiation and tumour growth; recent work has also shown that iron has a role in the tumour microenvironment and in metastasis. Pathways of iron acquisition, efflux, storage and regulation are all perturbed in cancer, suggesting that reprogramming of iron metabolism is a central aspect of tumour cell survival. Signalling through hypoxia-inducible factor (HIF) and WNT pathways may contribute to altered iron metabolism in cancer. Targeting iron metabolic pathways may provide new tools for cancer prognosis and therapy.
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Crichton, R. in Iron Metabolism: from Molecular Mechanisms to Cinical Consequences 17–58 (John Wiley and Sons, 2009).
Inoue, S. & Kawanishi, S. Hydroxyl radical production and human DNA damage induced by ferric nitrilotriacetate and hydrogen peroxide. Cancer Res. 47, 6522–6527 (1987).
Dizdaroglu, M., Rao, G., Halliwell, B. & Gajewski, E. Damage to the DNA bases in mammalian chromatin by hydrogen peroxide in the presence of ferric and cupric ions. Arch. Biochem. Biophys. 285, 317–324 (1991).
Dizdaroglu, M. & Jaruga, P. Mechanisms of free radical-induced damage to DNA. Free Radic. Res. 46, 382–419 (2012).
Campbell, J. A. Effects of precipitated silica and of iron oxide on the incidence of primary lung tumours in mice. Br. Med. J. 2, 275–280 (1940).
Richmond, H. G. Induction of sarcoma in the rat by iron-dextran complex. Br. Med. J. 1, 947–949 (1959).
Hann, H. W., Stahlhut, M. W. & Blumberg, B. S. Iron nutrition and tumor growth: decreased tumor growth in iron-deficient mice. Cancer Res. 48, 4168–4170 (1988).
Hann, H. W., Stahlhut, M. W. & Menduke, H. Iron enhances tumor growth. Observation on spontaneous mammary tumors in mice. Cancer 68, 2407–2410 (1991).
Stevens, R. G., Graubard, B. I., Micozzi, M. S., Neriishi, K. & Blumberg, B. S. Moderate elevation of body iron level and increased risk of cancer occurrence and death. Int. J. Cancer 56, 364–369 (1994).
Stevens, R. G., Jones, D. Y., Micozzi, M. S. & Taylor, P. R. Body iron stores and the risk of cancer. New Engl. J. Med. 319, 1047–1052 (1988).
van Asperen, I. A., Feskens, E. J., Bowles, C. H. & Kromhout, D. Body iron stores and mortality due to cancer and ischaemic heart disease: a 17-year follow-up study of elderly men and women. Int. J. Epidemiol. 24, 665–670 (1995).
Knekt, P. et al. Body iron stores and risk of cancer. Int. J. Cancer 56, 379–382 (1994).
Wu, T., Sempos, C. T., Freudenheim, J. L., Muti, P. & Smit, E. Serum iron, copper and zinc concentrations and risk of cancer mortality in US adults. Ann. Epidemiol. 14, 195–201 (2004).
Nelson, R. L. Iron and colorectal cancer risk: human studies. Nutr. Rev. 59, 140–148 (2001).
Kabat, G. C., Miller, A. B., Jain, M. & Rohan, T. E. Dietary iron and haem iron intake and risk of endometrial cancer: a prospective cohort study. Br. J. Cancer 98, 194–198 (2008).
Mursu, J., Robien, K., Harnack, L. J., Park, K. & Jacobs, D. R. Jr. Dietary supplements and mortality rate in older women: the Iowa Women's Health Study. Arch. Intern. Med. 171, 1625–1633 (2011).
Ward, M. H. et al. Heme iron from meat and risk of adenocarcinoma of the esophagus and stomach. Eur. J. Cancer Prev. 21, 134–138 (2012).
Cross, A. J., Pollock, J. R. & Bingham, S. A. Haem, not protein or inorganic iron, is responsible for endogenous intestinal N-nitrosation arising from red meat. Cancer Res. 63, 2358–2360 (2003).
Choi, J. Y. et al. Iron intake, oxidative stress-related genes (MnSOD and MPO) and prostate cancer risk in CARET cohort. Carcinogenesis 29, 964–970 (2008).
Hong, C. C. et al. Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol. Biomarkers Prev. 16, 1784–1794 (2007).
Pietrangelo, A. Hereditary hemochromatosis: pathogenesis, diagnosis, and treatment. Gastroenterology 139, 393–408 (2010).
Bradbear, R. A. et al. Cohort study of internal malignancy in genetic hemochromatosis and other chronic nonalcoholic liver diseases. J. Natl Cancer Inst. 75, 81–84 (1985).
Milman, N. et al. Clinically overt hereditary hemochromatosis in Denmark 1948-1985: epidemiology, factors of significance for long-term survival, and causes of death in 179 patients. Ann. Hematol. 80, 737–744 (2001).
Elmberg, M. et al. Cancer risk in patients with hereditary hemochromatosis and in their first-degree relatives. Gastroenterology 125, 1733–1741 (2003).
Niederau, C. et al. Survival and causes of death in cirrhotic and in noncirrhotic patients with primary hemochromatosis. N. Engl. J. Med. 313, 1256–1262 (1985).
Hsing, A. W. et al. Cancer risk following primary hemochromatosis: a population-based cohort study in Denmark. Int. J. Cancer 60, 160–162 (1995).
Osborne, N. J. et al. HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology 51, 1311–1318 (2010).
Edgren, G. et al. Donation frequency, iron loss, and risk of cancer among blood donors. J. Natl Cancer Inst. 100, 572–579 (2008).
Andrews, N. C. Forging a field: the golden age of iron biology. Blood 112, 219–230 (2008). Excellent overall review of recent advances in iron biology.
Daniels, T. R. et al. The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim. Biophys. Acta 1820, 291–317 (2012). Summary of past and current strategies used to target TFR1 for anticancer therapy.
Brooks, D. et al. Phase Ia trial of murine immunoglobulin A antitransferrin receptor antibody 42/6. Clin. Cancer Res. 1, 1259–1265 (1995).
Taetle, R., Castagnola, J. & Mendelsohn, J. Mechanisms of growth inhibition by anti-transferrin receptor monoclonal antibodies. Cancer Res. 46, 1759–1763 (1986).
Ohgami, R. S. et al. Identification of a ferrireductase required for efficient transferrin-dependent iron uptake in erythroid cells. Nature Genet. 37, 1264–1269 (2005).
Knutson, M. D. Steap proteins: implications for iron and copper metabolism. Nutr. Rev. 65, 335–340 (2007).
Leng, X., Wu, Y. & Arlinghaus, R. B. Relationships of lipocalin 2 with breast tumorigenesis and metastasis. J. Cell. Physiol. 226, 309–314 (2011).
Zhang, Y., Fan, Y. & Mei, Z. NGAL and NGALR overexpression in human hepatocellular carcinoma toward a molecular prognostic classification. Cancer Epidemiol. 36, e294–e299 (2012).
Leung, L. et al. Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma. PLoS ONE 7, e46677 (2012).
Saha, R., Saha, N., Donofrio, R. S. & Bestervelt, L. L. Microbial siderophores: a mini review. J. Basic Microbiol. 26 Jun 2012 (doi:10.1002/jobm.201100552).
Bao, G. et al. Iron traffics in circulation bound to a siderocalin (Ngal)-catechol complex. Nature Chem. Biol. 6, 602–609 (2010).
Devireddy, L. R., Hart, D. O., Goetz, D. H. & Green, M. R. A mammalian siderophore synthesized by an enzyme with a bacterial homolog involved in enterobactin production. Cell 141, 1006–1017 (2010). References 39 and 40 were the first to identify endogenous mammalian siderophores.
Fernandez, C. A. et al. The matrix metalloproteinase-9/neutrophil gelatinase-associated lipocalin complex plays a role in breast tumor growth and is present in the urine of breast cancer patients. Clin. Cancer Res. 11, 5390–5395 (2005).
Yang, J., McNeish, B., Butterfield, C. & Moses, M. A. Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J 27, 45–50 (2012).
Berger, T., Cheung, C. C., Elia, A. J. & Mak, T. W. Disruption of the Lcn2 gene in mice suppresses primary mammary tumor formation but does not decrease lung metastasis. Proc. Natl Acad. Sci. USA 107, 2995–3000 (2010).
Cramer, E. P. et al. No effect of NGAL/lipocalin-2 on aggressiveness of cancer in the MMTV-PyMT/FVB/N mouse model for breast cancer. PLoS ONE 7, e39646 (2012).
Lee, H. J. et al. Ectopic expression of neutrophil gelatinase-associated lipocalin suppresses the invasion and liver metastasis of colon cancer cells. Int. J. Cancer 118, 2490–2497 (2006).
Sun, Y. et al. NGAL expression is elevated in both colorectal adenoma-carcinoma sequence and cancer progression and enhances tumorigenesis in xenograft mouse models. Clin. Cancer Res. 17, 4331–4340 (2011).
Bauer, M. et al. Neutrophil gelatinase-associated lipocalin (NGAL) is a predictor of poor prognosis in human primary breast cancer. Breast Cancer Res. Treat. 108, 389–397 (2008).
Wenners, A. S. et al. Neutrophil gelatinase-associated lipocalin (NGAL) predicts response to neoadjuvant chemotherapy and clinical outcome in primary human breast cancer. PLoS ONE 7, e45826 (2012).
Wu, K. J., Polack, A. & Dalla-Favera, R. Coordinated regulation of iron-controlling genes, H-ferritin and IRP2, by c-MYC. Science 283, 676–679 (1999).
Radulescu, S. et al. Luminal iron levels govern intestinal tumorigenesis after apc loss in vivo. Cell Rep. 2, 270–282 (2012). This paper provides a mechanistic explanation of how excess iron contributes to intestinal tumorigenesis.
Tsuji, Y., Kwak, E., Saika, T., Torti, S. V. & Torti, F. M. Preferential repression of the H subunit of ferritin by adenovirus E1A in NIH-3T3 mouse fibroblasts. J. Biol. Chem. 268, 7270–7275 (1993).
Kakhlon, O., Gruenbaum, Y. & Cabantchik, Z. I. Repression of ferritin expression modulates cell responsiveness to H-ras-induced growth. Biochem. Soc. Trans. 30, 777–780 (2002).
Kakhlon, O., Gruenbaum, Y. & Cabantchik, Z. I. Ferritin expression modulates cell cycle dynamics and cell responsiveness to H-ras-induced growth via expansion of the labile iron pool. Biochem. J. 363, 431–436 (2002).
Zhang, F., Wang, W., Tsuji, Y., Torti, S. V. & Torti, F. M. Post-transcriptional modulation of iron homeostasis during p53-dependent growth arrest. J. Biol. Chem. 283, 33911–33918 (2008).
Tong, W. H. et al. The glycolytic shift in fumarate-hydratase-deficient kidney cancer lowers AMPK levels, increases anabolic propensities and lowers cellular iron levels. Cancer Cell 20, 315–327 (2011).
Shpyleva, S. I. et al. Role of ferritin alterations in human breast cancer cells. Breast Cancer Res. Treat. 126, 63–71 (2011).
Liu, X. et al. Heavy chain ferritin siRNA delivered by cationic liposomes increases sensitivity of cancer cells to chemotherapeutic agents. Cancer Res. 71, 2240–2249 (2011).
Karin, M. Nuclear factor-κB in cancer development and progression. Nature 441, 431–436 (2006).
Torti, S. V. et al. The molecular cloning and characterization of murine ferritin heavy chain, a tumor necrosis factor-inducible gene. J. Biol. Chem. 263, 12638–12644 (1988).
Kwak, E. L., Larochelle, D. A., Beaumont, C., Torti, S. V. & Torti, F. M. Role for NF-kappa B in the regulation of ferritin H by tumor necrosis factor-alpha. J. Biol. Chem. 270, 15285–15293 (1995).
Pham, C. G. et al. Ferritin heavy chain upregulation by NF-kappaB inhibits TNFalpha-induced apoptosis by suppressing reactive oxygen species. Cell 119, 529–542 (2004).
Ruddell, R. G. et al. Ferritin functions as a proinflammatory cytokine via iron-independent protein kinase C zeta/nuclear factor kappaB-regulated signaling in rat hepatic stellate cells. Hepatology 49, 887–900 (2009).
Alkhateeb, A. A., Han, B. & Connor, J. R. Ferritin stimulates breast cancer cells through an iron-independent mechanism and is localized within tumor-associated macrophages. Breast Cancer Res. Treat. 137, 733–744 (2013).
Cortes, D. F. et al. Differential gene expression in normal and transformed human mammary epithelial cells in response to oxidative stress. Free Radic. Biol. Med. 50, 1565–1574 (2011).
Nemeth, E. et al. Hepcidin regulates cellular iron efflux by binding to ferroportin and inducing its internalization. Science 306, 2090–2093 (2004). Ground-breaking study demonstrating that hepcidin binds to ferroportin and triggers its degradation.
Ganz, T. & Nemeth, E. Hepcidin and iron homeostasis. Biochim. Biophys. Acta 1823, 1434–1443 (2012).
Ward, D. M. & Kaplan, J. Ferroportin-mediated iron transport: expression and regulation. Biochim. Biophys. Acta 1823, 1426–1433 (2012).
Lonnerdal, B. Trace element transport in the mammary gland. Annu. Rev. Nutr. 27, 165–177 (2007).
Pinnix, Z. K. et al. Ferroportin and iron regulation in breast cancer progression and prognosis. Sci Transl Med 2, 43ra56 (2010). This paper demonstrates that levels of ferroportin affect breast cancer cell growth, are altered in patients with breast cancer and affect the prognosis of patients with breast cancer.
Jiang, X. P., Elliott, R. L. & Head, J. F. Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res. 30, 759–765 (2010).
Miller, L. D. et al. An iron regulatory gene signature predicts outcome in breast cancer. Cancer Res. 71, 6728–6737 (2011).
Weiss, G. & Goodnough, L. T. Anemia of chronic disease. N. Engl. J. Med. 352, 1011–1023 (2005).
Weinberg, E. D. & Miklossy, J. Iron withholding: a defense against disease. J. Alzheimers Dis. 13, 451–463 (2008).
Weinberg, E. D. Iron withholding: a defense against infection and neoplasia. Physiol. Rev. 64, 65–102 (1984).
Maes, K. et al. In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood 116, 3635–3644 (2010).
Hohaus, S. et al. Anemia in Hodgkin's lymphoma: the role of interleukin-6 and hepcidin. J. Clin. Oncol. 28, 2538–2543 (2010).
Hubert, N. & Hentze, M. W. Previously uncharacterized isoforms of divalent metal transporter (DMT)-1: implications for regulation and cellular function. Proc. Natl Acad. Sci. USA 99, 12345–12350 (2002).
Galy, B., Ferring-Appel, D., Kaden, S., Grone, H. J. & Hentze, M. W. Iron regulatory proteins are essential for intestinal function and control key iron absorption molecules in the duodenum. Cell. Metab. 7, 79–85 (2008).
Maffettone, C., Chen, G., Drozdov, I., Ouzounis, C. & Pantopoulos, K. Tumorigenic properties of iron regulatory protein 2 (IRP2) mediated by its specific 73-amino acids insert. PLoS ONE 5, e10163 (2010). This work suggests that IRPs can modify tumour growth in ways that are independent of their effects on iron metabolism.
Chen, G., Fillebeen, C., Wang, J. & Pantopoulos, K. Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis 28, 785–791 (2007).
Mantovani, A., Allavena, P., Sica, A. & Balkwill, F. Cancer-related inflammation. Nature 454, 436–444 (2008).
Recalcati, S. et al. Differential regulation of iron homeostasis during human macrophage polarized activation. Eur. J. Immunol. 40, 824–835 (2010).
Corna, G. et al. Polarization dictates iron handling by inflammatory and alternatively activated macrophages. Haematologica 95, 1814–1822 (2010).
Cohen, L. A. et al. Serum ferritin is derived primarily from macrophages through a nonclassical secretory pathway. Blood 116, 1574–1584 (2010).
Han, J. et al. Iron uptake mediated by binding of H-ferritin to the TIM-2 receptor in mouse cells. PLoS ONE 6, e23800 (2011).
Li, L. et al. Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc. Natl Acad. Sci. USA 107, 3505–3510 (2010).
Coffman, L. G. et al. Regulatory effects of ferritin on angiogenesis. Proc. Natl Acad. Sci. USA 106, 570–575 (2009). This paper demonstrates that extracellular ferritin can antagonize the activity of endogenous antiangiogenic proteins.
Tesfay, L., Huhn, A. J., Hatcher, H., Torti, F. M. & Torti, S. V. Ferritin blocks inhibitory effects of two-chain high molecular weight kininogen (HKa) on adhesion and survival signaling in endothelial cells. PLoS ONE 7, e40030 (2012).
Ackroyd, R., Shorthouse, A. J. & Stephenson, T. J. Gastric carcinoma in siblings with Friedreich's ataxia. Eur. J. Surg. Oncol. 22, 301–303 (1996).
Kidd, A. et al. Breast cancer in two sisters with Friedreich's ataxia. Eur. J. Surg. Oncol. 27, 512–514 (2001).
Lill, R. et al. The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim. Biophys. Acta 1823, 1491–1508 (2012). Review of recent advances in mechanisms of iron–sulphur cluster biogenesis.
Babcock, M. et al. Regulation of mitochondrial iron accumulation by Yfh1p, a putative homolog of frataxin. Science 276, 1709–1712 (1997).
Shoichet, S. A. et al. Frataxin promotes antioxidant defense in a thiol-dependent manner resulting in diminished malignant transformation in vitro. Hum. Mol. Genet. 11, 815–821 (2002).
Thierbach, R. et al. Targeted disruption of hepatic frataxin expression causes impaired mitochondrial function, decreased life span and tumor growth in mice. Hum. Mol. Genet. 14, 3857–3864 (2005).
Schulz, T. J. et al. Induction of oxidative metabolism by mitochondrial frataxin inhibits cancer growth: Otto Warburg revisited. J. Biol. Chem. 281, 977–981 (2006).
Thierbach, R. et al. The Friedreich's ataxia protein frataxin modulates DNA base excision repair in prokaryotes and mammals. Biochem. J. 432, 165–172 (2010).
Keith, B., Johnson, R. S. & Simon, M. C. HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nature Rev. Cancer 12, 9–22 (2012).
Semenza, G. L. HIF-1: upstream and downstream of cancer metabolism. Curr. Opin. Genet. Dev. 20, 51–56 (2010).
Wang, G. L. & Semenza, G. L. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood 82, 3610–3615 (1993).
Tacchini, L., Bianchi, L., Bernelli-Zazzera, A. & Cairo, G. Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J. Biol. Chem. 274, 24142–24146 (1999).
Lok, C. N. & Ponka, P. Identification of a hypoxia response element in the transferrin receptor gene. J. Biol. Chem. 274, 24147–24152 (1999).
Lee, P. J. et al. Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J. Biol. Chem. 272, 5375–5381 (1997).
Mukhopadhyay, C. K., Mazumder, B. & Fox, P. L. Role of hypoxia-inducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J. Biol. Chem. 275, 21048–21054 (2000).
Peyssonnaux, C. et al. Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J. Clin. Invest. 117, 1926–1932 (2007).
Mastrogiannaki, M. et al. HIF-2alpha, but not HIF-1alpha, promotes iron absorption in mice. J. Clin. Invest. 119, 1159–1166 (2009). This paper demonstrates the role of HIF2α in iron absorption.
Shah, Y. M., Matsubara, T., Ito, S., Yim, S. H. & Gonzalez, F. J. Intestinal hypoxia-inducible transcription factors are essential for iron absorption following iron deficiency. Cell. Metab. 9, 152–164 (2009).
Xue, X. et al. Hypoxia-inducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res. 72, 2285–2293 (2012).
Terada, N., Or, R., Szepesi, A., Lucas, J. J. & Gelfand, E. W. Definition of the roles for iron and essential fatty acids in cell cycle progression of normal human T lymphocytes. Exp. Cell Res. 204, 260–267 (1993).
Thelander, L. & Graslund, A. Mechanism of inhibition of mammalian ribonucleotide reductase by the iron chelate of 1-formylisoquinoline thiosemicarbazone. Destruction of the tyrosine free radical of the enzyme in an oxygen-requiring reaction. J. Biol. Chem. 258, 4063–4066 (1983).
Thelander, L., Graslund, A. & Thelander, M. Continual presence of oxygen and iron required for mammalian ribonucleotide reduction: possible regulation mechanism. Biochem. Biophys. Res. Commun. 110, 859–865 (1983).
Martin, L. K. et al. A dose escalation and pharmacodynamic study of triapine and radiation in patients with locally advanced pancreas cancer. Int. J. Radiat. Oncol. Biol. Phys. 84, e475–e481 (2012).
Yu, Y. et al. Iron chelators for the treatment of cancer. Curr. Med. Chem. 19, 2689–2702 (2012). Recent summary of progress and challenges in the development of iron chelators as anticancer therapeutics.
Tanaka, H. et al. A ribonucleotide reductase gene involved in a p53-dependent cell-cycle checkpoint for DNA damage. Nature 404, 42–49 (2000).
Shao, J. et al. In vitro characterization of enzymatic properties and inhibition of the p53R2 subunit of human ribonucleotide reductase. Cancer Res. 64, 1–6 (2004).
Smith, P. et al. 2.6 A X-ray crystal structure of human p53R2, a p53-inducible ribonucleotide reductase. Biochemistry 48, 11134–11141 (2009).
Netz, D. J. et al. Eukaryotic DNA polymerases require an iron-sulfur cluster for the formation of active complexes. Nature Chem. Biol. 8, 125–132 (2012).
Veatch, J. R., McMurray, M. A., Nelson, Z. W. & Gottschling, D. E. Mitochondrial dysfunction leads to nuclear genome instability via an iron-sulfur cluster defect. Cell 137, 1247–1258 (2009).
Rudolf, J., Makrantoni, V., Ingledew, W. J., Stark, M. J. R. & White, M. F. The DNA repair helicases XPD and FancJ have essential iron-sulfur domains. Mol. Cell 23, 801–808 (2006).
Karanja, K. K., Cox, S. W., Duxin, J. P., Stewart, S. A. & Campbell, J. L. DNA2 and EXO1 in replication-coupled, homology-directed repair and in the interplay between HDR and the FA/BRCA network. Cell Cycle 11, 3983–3996 (2012).
Barber, L. J. et al. RTEL1 maintains genomic stability by suppressing homologous recombination. Cell 135, 261–271 (2008).
Stehling, O. et al. MMS19 assembles iron-sulfur proteins required for DNA metabolism and genomic integrity. Science 337, 195–199 (2012). Identification of MMS19 as a scaffolding protein involved in the assembly of a subset of iron–sulphur cluster-containing proteins involved in genome integrity, and demonstration of the role of this pathway in the response to DNA damage.
Lorsbach, R. B. et al. TET1, a member of a novel protein family, is fused to MLL in acute myeloid leukemia containing the t(10;11)(q22;q23). Leukemia 17, 637–641 (2003).
Thomson, J. et al. Non-genotoxic carcinogen exposure induces defined changes in the 5-hydroxymethylome. Genome Biol. 13, R93 (2012).
Tahiliani, M. et al. Conversion of 5-methylcytosine to 5-hydroxymethylcytosine in mammalian DNA by MLL partner TET1. Science 324, 930–935 (2009).
Malumbres, M. & Barbacid, M. Cell cycle, CDKs and cancer: a changing paradigm. Nature Rev. Cancer 9, 153–166 (2009).
Kulp, K. S., Green, S. L. & Vulliet, P. R. Iron deprivation inhibits cyclin-dependent kinase activity and decreases cyclin D/CDK4 protein levels in asynchronous MDA-MB-453 human breast cancer cells. Exp. Cell Res. 229, 60–68 (1996).
Nurtjahja-Tjendraputra, E., Fu, D., Phang, J. M. & Richardson, D. R. Iron chelation regulates cyclin D1 expression via the proteasome: a link to iron deficiency-mediated growth suppression. Blood 109, 4045–4054 (2007).
Ornstein, D. L. & Zacharski, L. R. Iron stimulates urokinase plasminogen activator expression and activates NF-kappa B in human prostate cancer cells. Nutr. Cancer 58, 115–126 (2007).
Tsukamoto, H. Iron regulation of hepatic macrophage TNFalpha expression. Free Radic. Biol. Med. 32, 309–313 (2002).
Pang, H. et al. Crystal structure of human pirin: an iron-binding nuclear protein and transcription cofactor. J. Biol. Chem. 279, 1491–1498 (2004).
Yu, Y. & Richardson, D. R. Cellular iron depletion stimulates the JNK and p38 MAPK signaling transduction pathways, dissociation of ASK1-thioredoxin, and activation of ASK1. J. Biol. Chem. 286, 15413–15427 (2011).
Polakis, P. Wnt signaling and cancer. Genes Dev. 14, 1837–1851 (2000).
Klaus, A. & Birchmeier, W. Wnt signalling and its impact on development and cancer. Nature Rev. Cancer 8, 387–398 (2008).
Brookes, M. J. et al. A role for iron in Wnt signalling. Oncogene 27, 966–975 (2008). One of the first papers demonstrating the connection between iron and WNT signalling.
Seril, D. N. et al. Dietary iron supplementation enhances DSS-induced colitis and associated colorectal carcinoma development in mice. Dig. Dis. Sci. 47, 1266–1278 (2002).
Ilsley, J. N. et al. Dietary iron promotes azoxymethane-induced colon tumors in mice. Nutr. Cancer 49, 162–169 (2004).
Song, S. et al. Wnt inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Res. 71, 7628–7639 (2011).
Coombs, G. S. et al. Modulation of Wnt/beta-catenin signaling and proliferation by a ferrous iron chelator with therapeutic efficacy in genetically engineered mouse models of cancer. Oncogene 31, 213–225 (2012).
Ebina, Y. et al. Nephrotoxicity and renal cell carcinoma after use of iron- and aluminum-nitrilotriacetate complexes in rats. J. Natl Cancer Inst. 76, 107–113 (1986).
Hamazaki, S., Okada, S., Ebina, Y., Fujioka, M. & Midorikawa, O. Nephrotoxicity of ferric nitrilotriacetate. An electron-microscopic and metabolic study. Am. J. Pathol. 123, 343–350 (1986).
Li, J. L., Okada, S., Hamazaki, S., Ebina, Y. & Midorikawa, O. Subacute nephrotoxicity and induction of renal cell carcinoma in mice treated with ferric nitrilotriacetate. Cancer Res. 47, 1867–1869 (1987).
Toyokuni, S., Mori, T. & Dizdaroglu, M. DNA base modifications in renal chromatin of Wistar rats treated with a renal carcinogen, ferric nitrilotriacetate. Int. J. Cancer 57, 123–128 (1994).
Jiang, L. et al. Deletion and single nucleotide substitution at G.:C in the kidney of gpt delta transgenic mice after ferric nitrilotriacetate treatment. Cancer Sci. 97, 1159–1167 (2006).
Hiroyasu, M. et al. Specific allelic loss of p16 (INK4A) tumor suppressor gene after weeks of iron-mediated oxidative damage during rat renal carcinogenesis. Am. J. Pathol. 160, 419–424 (2002).
Akatsuka, S. et al. Fenton reaction induced cancer in wild type rats recapitulates genomic alterations observed in human cancer. PLoS ONE 7, e43403 (2012). This study establishes a direct connection between iron-induced genomic alterations and cancer.
Xu, Y. et al. Receptor-type protein tyrosine phosphatase beta (RPTP-beta) directly dephosphorylates and regulates hepatocyte growth factor receptor (HGFR/Met) function. J. Biol. Chem. 286, 15980–15988 (2011).
Yacyshyn, O. K. et al. Tyrosine phosphatase beta regulates angiopoietin-Tie2 signaling in human endothelial cells. Angiogenesis 12, 25–33 (2009).
Estrov, Z. et al. In vitro and in vivo effects of deferoxamine in neonatal acute leukemia. Blood 69, 757–761 (1987).
Yamasaki, T., Terai, S. & Sakaida, I. Deferoxamine for advanced hepatocellular carcinoma. N. Engl. J. Med. 365, 576–578 (2011).
Hatcher, H. C., Singh, R. N., Torti, F. M. & Torti, S. V. Synthetic and natural iron chelators: therapeutic potential and clinical use. Future Med. Chem. 1, 1643–1670 (2009).
Whitnall, M., Howard, J., Ponka, P. & Richardson, D. R. A class of iron chelators with a wide spectrum of potent antitumor activity that overcomes resistance to chemotherapeutics. Proc. Natl Acad. Sci. USA 103, 14901–14906 (2006).
Melotte, V. et al. The N-myc downstream regulated gene (NDRG) family: diverse functions, multiple applications. FASEB J. 24, 4153–4166 (2010).
Chen, Z. et al. The iron chelators Dp44mT and DFO inhibit TGF-beta-induced epithelial-mesenchymal transition via up-regulation of N-Myc downstream-regulated gene 1 (NDRG1). J. Biol. Chem. 287, 17016–17028 (2012).
Crepin, R. et al. Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. Cancer Res. 70, 5497–5506 (2010).
Hatcher, H., Planalp, R., Cho, J., Torti, F. M. & Torti, S. V. Curcumin: from ancient medicine to current clinical trials. Cell. Mol. Life Sci. 65, 1631–1652 (2008).
Jiao, Y. et al. Iron chelation in the biological activity of curcumin. Free Radic. Biol. Med. 40, 1152–1160 (2006).
Jiao, Y. et al. Curcumin, a cancer chemopreventive and chemotherapeutic agent, is a biologically active iron chelator. Blood 113, 462–469 (2009).
Lin, L. et al. Antitumor agents. 250. Design and synthesis of new curcumin analogues as potential anti-prostate cancer agents. J. Med. Chem. 49, 3963–3972 (2006).
Adams, B. K. et al. Synthesis and biological evaluation of novel curcumin analogs as anti-cancer and anti-angiogenesis agents. Bioorg. Med. Chem. 12, 3871–3883 (2004).
Chen, X. et al. Chemoprevention of 7,12-dimethylbenz[a]anthracene (DMBA)-induced hamster cheek pouch carcinogenesis by a 5-lipoxygenase inhibitor, garcinol. Nutr. Cancer 64, 1211–1218 (2012).
Hanahan, D. & Weinberg, R. A. Hallmarks of cancer: the next generation. Cell 144, 646–674 (2011).
Cozzi, A. et al. Overexpression of wild type and mutated human ferritin H-chain in HeLa cells: in vivo role of ferritin ferroxidase activity. J. Biol. Chem. 275, 25122–25129 (2000).
Cozzi, A. et al. Analysis of the biologic functions of H− and L-ferritins in HeLa cells by transfection with siRNAs and cDNAs: evidence for a proliferative role of L-ferritin. Blood 103, 2377–2383 (2004).
Wang, W., Knovich, M. A., Coffman, L. G., Torti, F. M. & Torti, S. V. Serum ferritin: Past, present and future. Biochim. Biophys. Acta 1800, 760–769 (2010).
Jezequel, P. et al. Validation of tumor-associated macrophage ferritin light chain as a prognostic biomarker in node-negative breast cancer tumors: A multicentric 2004 national PHRC study. Int. J. Cancer 131, 426–437 (2012).
Carpagnano, G. E. et al. Could exhaled ferritin and SOD be used as markers for lung cancer and prognosis prediction purposes? Eur. J. Clin. Invest. 42, 478–486 (2012).
Kim, Y. et al. Targeting the Wnt/beta-catenin pathway with the antifungal agent ciclopirox olamine in a murine myeloma model. In Vivo 25, 887–893 (2011).
Chifman, J. et al. The core control system of intracellular iron homeostasis: a mathematical model. J. Theor. Biol. 300, 91–99 (2012).
Laubenbacher, R. et al. A systems biology view of cancer. Biochim. Biophys. Acta 1796, 129–139 (2009).
Hower, V. et al. A general map of iron metabolism and tissue-specific subnetworks. Mol. Biosyst 5, 422–443 (2009).
Sanchez, M., Galy, B., Muckenthaler, M. U. & Hentze, M. W. Iron-regulatory proteins limit hypoxia-inducible factor-2alpha expression in iron deficiency. Nature Struct. Mol. Biol. 14, 420–426 (2007).
Abeysinghe, R. D. et al. p53-independent apoptosis mediated by tachpyridine, an anti-cancer iron chelator. Carcinogenesis 22, 1607–1614 (2001).
Lui, G. Y. et al. The iron chelator, deferasirox, as a novel strategy for cancer treatment: oral activity against human lung tumor xenografts and molecular mechanism of action. Mol. Pharmacol. 83, 179–190 (2013).
Liu, Y. T. et al. Chronic oxidative stress causes amplification and overexpression of ptprz1 protein tyrosine phosphatase to activate beta-catenin pathway. Am. J. Pathol. 171, 1978–1988 (2007).
Ba, Q. et al. Iron deprivation suppresses hepatocellular carcinoma growth in experimental studies. Clin. Cancer Res. 17, 7625–7633 (2011).
Fracanzani, A. L. et al. Increased cancer risk in a cohort of 230 patients with hereditary hemochromatosis in comparison to matched control patients with non-iron-related chronic liver disease. Hepatology 33, 647–651 (2001).
Hann, H. W., Stahlhut, M. W. & Hann, C. L. Effect of iron and desferoxamine on cell growth and in vitro ferritin synthesis in human hepatoma cell lines. Hepatology 11, 566–569 (1990).
Boult, J. et al. Overexpression of cellular iron import proteins is associated with malignant progression of esophageal adenocarcinoma. Clin. Cancer Res. 14, 379–387 (2008).
Yue, J. et al. Transferrin-conjugated micelles: enhanced accumulation and antitumor effect for transferrin-receptor-overexpressing cancer models. Mol. Pharm. 9, 1919–1931 (2012).
Brookes, M. J. et al. Modulation of iron transport proteins in human colorectal carcinogenesis. Gut 55, 1449–1460 (2006).
Eberhard, Y. et al. Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood 114, 3064–3073 (2009).
Torti, S. V. et al. Tumor cell cytotoxicity of a novel metal chelator. Blood 92, 1384–1389 (1998).
Zhou, H. et al. The antitumor activity of the fungicide ciclopirox. Int. J. Cancer 127, 2467–2477 (2010).
Greene, B. T. et al. Activation of caspase pathways during iron chelator-mediated apoptosis. J. Biol. Chem. 277, 25568–25575 (2002).
Turner, J. et al. Tachpyridine, a metal chelator, induces G2 cell-cycle arrest, activates checkpoint kinases, and sensitizes cells to ionizing radiation. Blood 106, 3191–3199 (2005).
Kovacevic, Z., Chikhani, S., Lovejoy, D. B. & Richardson, D. R. Novel thiosemicarbazone iron chelators induce up-regulation and phosphorylation of the metastasis suppressor N-myc down-stream regulated gene 1: a new strategy for the treatment of pancreatic cancer. Mol. Pharmacol. 80, 598–609 (2011).
Yu, Y., Suryo Rahmanto, Y. & Richardson, D. R. Bp44mT: an orally active iron chelator of the thiosemicarbazone class with potent anti-tumour efficacy. Br. J. Pharmacol. 165, 148–166 (2012).
Fukushima, T. et al. Iron chelation therapy with deferasirox induced complete remission in a patient with chemotherapy-resistant acute monocytic leukemia. Anticancer Res. 31, 1741–1744 (2011).
Yen, Y. et al. A phase I trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone in combination with gemcitabine for patients with advanced cancer. Cancer Chemother. Pharmacol. 54, 331–342 (2004).
Knox, J. J. et al. Phase II study of Triapine in patients with metastatic renal cell carcinoma: a trial of the National Cancer Institute of Canada Clinical Trials Group (NCIC IND.161). Invest. New Drugs 25, 471–477 (2007).
Ma, B. et al. A multicenter phase II trial of 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, Triapine) and gemcitabine in advanced non-small-cell lung cancer with pharmacokinetic evaluation using peripheral blood mononuclear cells. Invest. New Drugs 26, 169–173 (2008).
Chao, J. et al. A phase I and pharmacokinetic study of oral 3-aminopyridine-2-carboxaldehyde thiosemicarbazone (3-AP, NSC #663249) in the treatment of advanced-stage solid cancers: a California Cancer Consortium Study. Cancer Chemother. Pharmacol. 69, 835–843 (2012).
Supported in part by grants R01 CA171101 (F.M.T.) and R01DK071892 (S.V.T.) from the US National Institutes of Health.
The authors declare no competing financial interests.
- Fenton reaction
A chemical reaction in which ferrous iron reacts with hydrogen peroxide to produce the hydroxyl radical. Iron oxidized during this reaction can be reduced back to ferrous iron in the presence of superoxide (a by-product of respiration). The sum of these reactions is the iron-catalysed formation of hydroxyl radicals from superoxide (termed the Haber–Weiss reaction).
A low molecular mass compound that has a high affinity for chelating iron.
- Iron–sulphur clusters
Assemblies of iron and inorganic sulphur that function as protein cofactors.
- Hereditary haemochromatosis
Inherited disorder caused by mutations in several different genes that leads to the accumulation of iron to excess levels in parenchymal tissues.
Drawing or removing blood from the circulation.
Intestinal epithelial cells that have major roles in the absorption of nutrients, including iron.
- Iron recycling
Reuse of cellular iron. Typically occurs through the catabolism of senescent red blood cells by macrophages of the liver and spleen.
- Friedreich's ataxia
Inherited disorder of the neurodegenerative system.
- Warburg effect
The propensity of cancer cells to shift from aerobic respiration to glycolysis for the generation of ATP, even in the presence of adequate oxygen levels. The name derives from the hypothesis proposed by Otto Warburg in 1924 that cancer is driven by the non-oxidative breakdown of glucose.
- Acyl hydrazones
Chemical substances containing oxygen and nitrogen donor ligands that coordinate iron.
Decreasing the number of cancer cells.
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Torti, S., Torti, F. Iron and cancer: more ore to be mined. Nat Rev Cancer 13, 342–355 (2013). https://doi.org/10.1038/nrc3495
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