Iron homeostasis and tumorigenesis: molecular mechanisms and therapeutic opportunities

Abstract

Excess iron is tightly associated with tumorigenesis in multiple human cancer types through a variety of mechanisms including catalyzing the formation of mutagenic hydroxyl radicals, regulating DNA replication, repair and cell cycle progression, affecting signal transduction in cancer cells, and acting as an essential nutrient for proliferating tumor cells. Thus, multiple therapeutic strategies based on iron deprivation have been developed in cancer therapy. During the past few years, our understanding of genetic association and molecular mechanisms between iron and tumorigenesis has expanded enormously. In this review, we briefly summarize iron homeostasis in mammals, and discuss recent progresses in understanding the aberrant iron metabolism in numerous cancer types, with a focus on studies revealing altered signal transduction in cancer cells.

Key words： Iron tumorigenesis; p53; Wnt; DNA repair; cell cycle

References

1 Chaston TB, Richardson DR (2003) Iron chelators for the treatment of iron overload disease: relationship between structure, redox activity, and toxicity. Am J Hematol73: 200-210

2 Chen G, Fillebeen C, Wang J, Pantopoulos K (2007) Overexpression of iron regulatory protein 1 suppresses growth of tumor xenografts. Carcinogenesis28: 785-791

3 Chen Y, Zhang Z, Yang K, Du J, Xu Y, Liu S (2014) Myeloid zincfinger 1 (MZF-1) suppresses prostate tumor growth through enforcing ferroportin-conducted iron egress. Oncogene

4 Cheng Z, Dai LL, Song YN, Kang Y, Si JM, Xia J, Liu YF (2014) Regulatory effect of iron regulatory protein-2 on iron metabolism in lung cancer. Genet Mol Res13: 5514-5522

5 Cho H, Kim JH (2009) Lipocalin2 expressions correlate significantly with tumor differentiation in epithelial ovarian cancer. J Histochem Cytochem57: 513-521

6 Choi AM, Alam J (1996) Heme oxygenase-1: function, regulation, and implication of a novel stress-inducible protein in oxidantinduced lung injury. Am J Respir Cell Mol Biol15: 9-19

7 Crepin R, Goenaga AL, Jullienne B, Bougherara H, Legay C, Benihoud K, Marks JD, Poul MA (2010) Development of human single-chain antibodies to the transferrin receptor that effectively antagonize the growth of leukemias and lymphomas. Cancer Res70: 5497-5506

8 Daniels TR, Bernabeu E, Rodriguez JA, Patel S, Kozman M, Chiappetta DA, Holler E, Ljubimova JY, Helguera G, Penichet ML (2012) The transferrin receptor and the targeted delivery of therapeutic agents against cancer. Biochim Biophys Acta1820: 291-317

9 Dayani PN, Bishop MC, Black K, Zeltzer PM (2004) Desferoxamine (DFO)-mediated iron chelation: rationale for a novel approach to therapy for brain cancer. J Neurooncol67: 367-377

10 Denic S, Agarwal MM (2007) Nutritional iron deficiency: an evolutionary perspective. Nutrition23: 603-614

11 Dongiovanni P, Fracanzani AL, Cairo G, Megazzini CP, Gatti S, Rametta R, Fargion S, Valenti L (2010) Iron-dependent regulation of MDM2 influences p53 activity and hepatic carcinogenesis. Am J Pathol176: 1006-1017

12 Duarte DC, Nicolau A, Teixeira JA, Rodrigues LR (2011) The effect of bovine milk lactoferrin on human breast cancer cell lines. J Dairy Sci94: 66-76

13 Dunn LL, Suryo Rahmanto Y, Richardson DR (2007) Iron uptake and metabolism in the new millennium. Trends Cell Biol17: 93-100

14 Eberhard Y, McDermott SP, Wang X, Gronda M, Venugopal A, Wood TE, Hurren R, Datti A, Batey RA, Wrana J (2009) Chelation of intracellular iron with the antifungal agent ciclopirox olamine induces cell death in leukemia and myeloma cells. Blood114: 3064-3073

15 Emanuele D, Tuason I, Edwards QT (2014) HFE-associated hereditary hemochromatosis: overview of genetics and clinical implications for nurse practitioners in primary care settings. J Am Assoc Nurse Pract26: 113-122

16 Enyedy EA, Primik MF, Kowol CR, Arion VB, Kiss T, Keppler BK (2011) Interaction of Triapine and related thiosemicarbazones with iron(III)/(II) and gallium(III): a comparative solution equilibrium study. Dalton Trans40: 5895-5905

17 Fernandez CA, Yan L, Louis G, Yang J, Kutok JL, Moses MA (2005) 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 Res11: 5390-5395

18 Forsythe JA, Jiang BH, Iyer NV, Agani F, Leung SW, Koos RD, Semenza GL (1996) Activation of vascular endothelial growth factor gene transcription by hypoxia-inducible factor 1. Mol Cell Biol16: 4604-4613

19 Fu D, Richardson DR (2007) Iron chelation and regulation of the cell cycle: 2 mechanisms of posttranscriptional regulation of the universal cyclin-dependent kinase inhibitor p21CIP1/WAF1 by iron depletion. Blood110: 752-761

20 Gkouvatsos K, Papanikolaou G, Pantopoulos K (2012) Regulation of iron transport and the role of transferrin. Biochim Biophys Acta1820: 188-202

21 Hamalainen P, Saltevo J, Kautiainen H, Mantyselka P, Vanhala M (2012) Erythropoietin, ferritin, haptoglobin, hemoglobin and transferrin receptor in metabolic syndrome: a case control study. Cardiovasc Diabetol11: 116

22 Hewitson KS, McNeill LA, Elkins JM, Schofield CJ (2003) The role of iron and 2-oxoglutarate oxygenases in signalling. Biochem Soc Trans31: 510-515

23 Hohaus S, Massini G, Giachelia M, Vannata B, Bozzoli V, Cuccaro A, D’Alo F, Larocca LM, Raymakers RA, Swinkels DW (2010) Anemia in Hodgkin’s lymphoma: the role of interleukin-6 and hepcidin. J Clin Oncol28: 2538-2543

24 Hong CC, Ambrosone CB, Ahn J, Choi JY, McCullough ML, Stevens VL, Rodriguez C, Thun MJ, Calle EE (2007) Genetic variability in iron-related oxidative stress pathways (Nrf2, NQ01, NOS3, and HO-1), iron intake, and risk of postmenopausal breast cancer. Cancer Epidemiol Biomark Prev16: 1784-1794

25 Hou Y, Zhang S, Wang L, Li J, Qu G, He J, Rong H, Ji H, Liu S (2012) Estrogen regulates iron homeostasis through governing hepatic hepcidin expression via an estrogen response element. Gene511: 398-403

26 Iwasaki K, Ray PD, Huang BW, Sakamoto K, Kobayashi T, Tsuji Y (2013) Role of AMP-activated protein kinase in ferritin H gene expression by resveratrol in human T cells. Biochemistry52: 5075-5083

27 Jakszyn PG, Allen NE, Lujan-Barroso L, Gonzalez CA, Key TJ, Fonseca-Nunes A, Tjonneland A, Fons-Johnsen N, Overvad K, Teucher B (2012) Nitrosamines and heme iron and risk of prostate cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomark Prev21: 547-551

28 Jiang XP, Elliott RL, Head JF (2010) Manipulation of iron transporter genes results in the suppression of human and mouse mammary adenocarcinomas. Anticancer Res30: 759-765

29 Josson S, Matsuoka Y, Gururajan M, Nomura T, Huang WC, Yang X, Lin JT, Bridgman R, Chu CY, Johnstone PA (2013) Inhibition of beta2-microglobulin/hemochromatosis enhances radiation sensitivity by induction of iron overload in prostate cancer cells. PLoS One8: e68366

30 Kalousova M, Krechler T, Jachymova M, Kubena AA, Zak A, Zima T (2012) Ferritin as an independent mortality predictor in patients with pancreas cancer. Results of a pilot study. Tumour Biol33: 1695-1700

31 Kaplan CD, Kaplan J (2009) Iron acquisition and transcriptional regulation. Chem Rev109: 4536-4552

32 Keith B, Johnson RS, Simon MC (2012) HIF1alpha and HIF2alpha: sibling rivalry in hypoxic tumour growth and progression. Nat Rev Cancer12: 9-22

33 Koc M, Taysi S, Sezen O, Bakan N (2003) Levels of some acutephase proteins in the serum of patients with cancer during radiotherapy. Biol Pharm Bull26: 1494-1497

34 Koreth J, Antin JH (2010) Iron overload in hematologic malignancies and outcome of allogeneic hematopoietic stem cell transplantation. Haematologica95: 364-366

35 Kowdley KV (2004) Iron, hemochromatosis, and hepatocellular carcinoma. Gastroenterology127: S79-86

36 Kukulj S, Jaganjac M, Boranic M, Krizanac S, Santic Z, Poljak-Blazi M (2010) Altered iron metabolism, inflammation, transferrin receptors, and ferritin expression in non-small-cell lung cancer. Med Oncol27: 268-277

37 Kumar D, Viberg J, Nilsson AK, Chabes A (2010) Highly mutagenic and severely imbalanced dNTP pools can escape detection by the S-phase checkpoint. Nucleic Acids Res38: 3975-3983

38 Lee PJ, Jiang BH, Chin BY, Iyer NV, Alam J, Semenza GL, Choi AM (1997) Hypoxia-inducible factor-1 mediates transcriptional activation of the heme oxygenase-1 gene in response to hypoxia. J Biol Chem272: 5375-5381

39 Lee SH, Pyo CW, Hahm DH, Kim J, Choi SY (2009) Iron-saturated lactoferrin stimulates cell cycle progression through PI3K/Akt pathway. Mol Cells28: 37-42

40 Leng X, Ding T, Lin H, Wang Y, Hu L, Hu J, Feig B, Zhang W, Pusztai L, Symmans WF (2009) Inhibition of lipocalin 2 impairs breast tumorigenesis and metastasis. Cancer Res69: 8579-8584

41 Leng X, Wu Y, Arlinghaus RB (2011) Relationships of lipocalin 2 with breast tumorigenesis and metastasis. J Cell Physiol226: 309-314

42 Leung L, Radulovich N, Zhu CQ, Organ S, Bandarchi B, Pintilie M, To C, Panchal D, Tsao MS (2012) Lipocalin2 promotes invasion, tumorigenicity and gemcitabine resistance in pancreatic ductal adenocarcinoma. PLoS One7: e46677

43 Lill R, Hoffmann B, Molik S, Pierik AJ, Rietzschel N, Stehling O, Uzarska MA, Webert H, Wilbrecht C, Muhlenhoff U (2012) The role of mitochondria in cellular iron-sulfur protein biogenesis and iron metabolism. Biochim Biophys Acta1823: 1491-1508

44 Lin X, Yang H, Zhou L, Guo Z (2011) Nrf2-dependent induction of NQO1 in mouse aortic endothelial cells overexpressing catalase. Free Radic Biol Med51: 97-106

45 Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem274: 24147-24152

46 Lovejoy DB, Richardson DR (2003) Iron chelators as anti-neoplastic agents: current developments and promise of the PIH class of chelators. Curr Med Chem10: 1035-1049

47 MacDonald BT, Tamai K, He X (2009) Wnt/beta-catenin signaling: components, mechanisms, and diseases. Dev Cell17: 9-26

48 MacKenzie EL, Iwasaki K, Tsuji Y (2008) Intracellular iron transport and storage: from molecular mechanisms to health implications. Antioxid Redox Signal10: 997-1030

49 Maes K, Nemeth E, Roodman GD, Huston A, Esteve F, Freytes C, Callander N, Katodritou E, Tussing-Humphreys L, Rivera S (2010) In anemia of multiple myeloma, hepcidin is induced by increased bone morphogenetic protein 2. Blood116: 3635-3644

50 Mannelqvist M, Stefansson IM, Wik E, Kusonmano K, Raeder MB, Oyan AM, Kalland KH, Moses MA, Salvesen HB, Akslen LA (2012) Lipocalin 2 expression is associated with aggressive features of endometrial cancer. BMC Cancer12: 169

51 Mantovani A, Allavena P, Sica A, Balkwill F (2008) Cancer-related inflammation. Nature454: 436-444

52 Martin JH, Alalami O, Yaqoob F (2000) Differential effects of retinoids on nitric oxide production by promonocytic U937 cells and ZR-75-1 human breast cancer cells. Oncol Rep7: 219-223

53 Miller JL (2013) Iron deficiency anemia: a common and curable disease. Cold Spring Harb Perspect Med3: a011866

54 Miyabe I, Kunkel TA, Carr AM (2011) The major roles of DNA polymerases epsilon and delta at the eukaryotic replication fork are evolutionarily conserved. PLoS Genet7: e1002407

55 Molina-Montes E, Wark PA, Sanchez MJ, Norat T, Jakszyn P, LujanBarroso L, Michaud DS, Crowe F, Allen N, Khaw KT (2012) Dietary intake of iron, heme-iron and magnesium and pancreatic cancer risk in the European prospective investigation into cancer and nutrition cohort. Int J Cancer131: E1134-1147

56 Moser JC, Rawal M, Wagner BA, Du J, Cullen JJ, Buettner GR (2013) Pharmacological ascorbate and ionizing radiation (IR) increase labile iron in pancreatic cancer. Redox Biol2: 22-27

57 Muckenthaler MU, Galy B, Hentze MW (2008) Systemic iron homeostasis and the iron-responsive element/iron-regulatory protein (IRE/IRP) regulatory network. Annu Rev Nutr28: 197-213

58 Mukhopadhyay CK, Mazumder B, Fox PL (2000) Role of hypoxiainducible factor-1 in transcriptional activation of ceruloplasmin by iron deficiency. J Biol Chem275: 21048-21054

59 Munoz M, Gomez-Ramirez S, Martin-Montanez E, Auerbach M (2014) Perioperative anemia management in colorectal cancer patients: a pragmatic approach. World J Gastroenterol20: 1972-1985

60 Oh WK (2002) The evolving role of estrogen therapy in prostate cancer. Clin Prostate Cancer1: 81 -89

61 Ornstein DL, Zacharski LR (2007) Iron stimulates urokinase plasminogen activator expression and activates NF-kappa B in human prostate cancer cells. Nutr Cancer58: 115-126

62 Orrenius S, Nicotera P, Zhivotovsky B (2011) Cell death mechanisms and their implications in toxicology. Toxicol Sci119: 3-19

63 Osborne NJ, Gurrin LC, Allen KJ, Constantine CC, Delatycki MB, McLaren CE, Gertig DM, Anderson GJ, Southey MC, Olynyk JK (2010) HFE C282Y homozygotes are at increased risk of breast and colorectal cancer. Hepatology51: 1311 -1318

64 Pantopoulos K, Porwal SK, Tartakoff A, Devireddy L (2012) Mechanisms of mammalian iron homeostasis. Biochemistry 51: 5705-5724

65 Park KS, Kim H, Kim NG, Cho SY, Choi KH, Seong JK, Paik YK (2002) Proteomic analysis and molecular characterization of tissue ferritin light chain in hepatocellular carcinoma. Hepatology35: 1459-1466

66 Peyssonnaux C, Zinkernagel AS, Schuepbach RA, Rankin E, Vaulont S, Haase VH, Nizet V, Johnson RS (2007) Regulation of iron homeostasis by the hypoxia-inducible transcription factors (HIFs). J Clin Invest117: 1926-1932

67 Preston BD, Albertson TM, Herr AJ (2010) DNA replication fidelity and cancer. Semin Cancer Biol20: 281 -293

68 Pusatcioglu CK, Nemeth E, Fantuzzi G, Llor X, Freels S, TussingHumphreys L, Cabay RJ, Linzmeier R, Ng D, Clark J (2014) Systemic and tumor level iron regulation in men with colorectal cancer: a case control study. Nutr Metab (Lond)11: 21

69 Radulescu S, Brookes MJ, Salgueiro P, Ridgway RA, McGhee E, Anderson K, Ford SJ, Stones DH, Iqbal TH, Tselepis C (2012) Luminal iron levels govern intestinal tumorigenesis after Apc loss in vivo. Cell Rep2: 270-282

70 Richardson DR, Kalinowski DS, Richardson V, Sharpe PC, Lovejoy DB, Islam M, Bernhardt PV (2009) 2-Acetylpyridine thiosemicarbazones are potent iron chelators and antiproliferative agents: redox activity, iron complexation and characterization of their antitumor activity. J Med Chem52: 1459-1470

71 Romero A, Ramos E, de Los Rios C, Egea J, Del Pino J, Reiter RJ (2014) A review of metal-catalyzed molecular damage: protection by melatonin. J Pineal Res56: 343-370

72 Rossi E (2005) Hepcidin – the iron regulatory hormone. Clin Biochem Rev26: 47-49

73 Rouault TA (2003) How mammals acquire and distribute iron needed for oxygen-based metabolism. PLoS Biol1: E79

74 Rouault TA (2006) The role of iron regulatory proteins in mammalian iron homeostasis and disease. Nat Chem Biol2: 406-414

75 Sakurai K, Sohda T, Ueda S, Tanaka T, Hirano G, Yokoyama K, Mori hara D, Aanan A, Takeyama Y, Irie M (2014) Immunohistochemi cal demonstration of transferri n receptor 1 and 2 in human hepatocellular carcinoma tissue. Hepatogastroenterology61: 426-430

76 Sarkar A, Sil PC (2014) Iron oxide nanoparticles mediated cytotoxicity via PI3K/AKT pathway: role of quercetin. Food Chem Toxicol71: 106-115

77 Shen J, Sheng X, Chang Z, Wu Q, Wang S, Xuan Z, Li D, Wu Y, Shang Y, Kong X (2014) Iron metabolism regulates p53 signaling through direct heme-p53 interaction and modulation of p53 localization, stability, and function. Cell Rep7: 180-193

78 Shiiba M, Saito K, Fushimi K, Ishigami T, Shinozuka K, Nakashima D, Kouzu Y, Koike H, Kasamatsu A, Sakamoto Y (2013) Lipocalin-2 is associated with radioresistance in oral cancer and lung cancer cells. Int J Oncol42: 1197-1204

79 Shpyleva SI, Tryndyak VP, Kovalchuk O, Starlard-Davenport A, Chekhun VF, Beland FA, Pogribny IP (2011) Role of ferritin alterations in human breast cancer cells. Breast Cancer Res Treat126: 63-71

80 Sica A, Allavena P, Mantovani A (2008) Cancer related inflammation: the macrophage connection. Cancer Lett267: 204-215

81 Siriwardana G, Seligman PA (2013) Two cell cycle blocks caused by iron chelation of neuroblastoma cells: separating cell cycle events associated with each block. Physiol Rep1: e00176

82 Song S, Christova T, Perusini S, Alizadeh S, Bao RY, Miller BW, Hurren R, Jitkova Y, Gronda M, Isaac M (2011) Wnt inhibitor screen reveals iron dependence of beta-catenin signaling in cancers. Cancer Res71: 7628-7639

83 Stocker R (1990) Induction of haem oxygenase as a defence against oxidative stress. Free Radic Res Commun9: 101 -112

84 Tacchini L, Bianchi L, Bernelli-Zazzera A, Cairo G (1999) Transferrin receptor induction by hypoxia. HIF-1-mediated transcriptional activation and cell-specific post-transcriptional regulation. J Biol Chem274: 24142-24146

85 Tammariello AE, Milner JA (2010) Mouse models for unraveling the importance of diet in colon cancer prevention. J Nutr Biochem21: 77-88

86 Tan MG, Kumarasinghe MP, Wang SM, Ooi LL, Aw SE, Hui KM (2009) Modulation of iron-regulatory genes in human hepatocellular carcinoma and its physiological consequences. Exp Biol Med (Maywood)234: 693-702

87 Tenga MJ, Lazar IM (2014) Proteomic study reveals a functional network of cancer markers in the G1-Stage of the breast cancer cell cycle. BMC Cancer14: 710

88 Thomas C, Mackey MM, Diaz AA, Cox DP (2009) Hydroxyl radical is produced via the Fenton reaction in submitochondrial particles under oxidative stress: implications for diseases associated with iron accumulation. Redox Rep14: 102-108

89 Torti SV, Torti FM (2013) Iron and cancer: more ore to be mined. Nat Rev Cancer13: 342-355

90 Trachootham D, Lu W, Ogasawara MA, Nilsa RD, Huang P (2008) Redox regulation of cell survival. Antioxid Redox Signal10: 1343-1374

91 Tsui KH, Chung LC, Wang SW, Feng TH, Chang PL, Juang HH (2013) Hypoxia upregulates the gene expression of mitochondrial aconitase in prostate carcinoma cells. J Mol Endocrinol51: 131 -141

92 Vakkala M, Paakko P, Soini Y (2000) eNOS expression is associated with the estrogen and progesterone receptor status in invasive breast carcinoma. Int J Oncol17: 667-671

93 Valerio LG (2007) Mammalian iron metabolism. Toxicol Mech. Methods17: 497-517

94 Vescio RA, Connors KM, Bordin GM, Robb JA, Youngkin T, Umbreit JN, Hoffman RM (1990) The distinction of small cell and nonsmall cell lung cancer by growth in native-state histoculture. Cancer Res50: 6095-6099

95 von Maltzahn J, Chang NC, Bentzinger CF, Rudnicki MA (2012) Wnt signaling in myogenesis. Trends Cell Biol22: 602-609

96 Wang J, Pantopoulos K (2002) Conditional derepression of ferritin synthesis in cells expressing a constitutive IRP1 mutant. Mol Cell Biol22: 4638-4651

97 Wang J, Li Q, Ou Y, Han Z, Li K, Wang P, Zhou S (2011) Inhibition of tumor growth by recombinant adenovirus containing human lactoferrin through inducing tumor cell apoptosis in mice bearing EMT6 breast cancer. Arch Pharm Res34: 987-995

98 Wang N, Wei H, Yin D, Lu Y, Zhang Y, Jiang D, Jiang Y, Zhang S (2014) Cyclin D1b overexpression inhibits cell proliferation and induces cell apoptosis in cervical cancer cells in vitro and in vivo. Int J Clin Exp Pathol7: 4016-4023

99 Ward PP, Mendoza-Meneses M, Cunningham GA, Conneely OM (2003) Iron status in mice carrying a targeted disruption of lactoferrin. Mol Cell Biol23: 178-185

100 Wu Y, Brosh RM Jr (2012) DNA helicase and helicase-nuclease enzymes with a conserved iron-sulfur cluster. Nucleic Acids Res40: 4247-4260

101 Wyllie S, Liehr JG (1997) Release of iron from ferritin storage by redox cycling of stilbene and steroid estrogen metabolites: a mechanism of induction of free radical damage by estrogen. Arch Biochem Biophys346: 180-186

102 Xiong W, Wang L, Yu F (2014) Regulation of cellular iron metabolism and its implications in lung cancer progression. Med Oncol31: 28

103 Xue X, Shah YM (2013) Intestinal iron homeostasis and colon tumorigenesis. Nutrients5: 2333-2351

104 Xue X, Taylor M, Anderson E, Hao C, Qu A, Greenson JK, Zimmermann EM, Gonzalez FJ, Shah YM (2012) Hypoxiainducible factor-2alpha activation promotes colorectal cancer progression by dysregulating iron homeostasis. Cancer Res72: 2285-2293

105 Yang J, Bielenberg DR, Rodig SJ, Doiron R, Clifton MC, Kung AL, Strong RK, Zurakowski D, Moses MA (2009) Lipocalin 2 promotes breast cancer progression. Proc Natl Acad Sci U S A106: 3913-3918

106 Yang J, McNeish B, Butterfield C, Moses MA (2013) Lipocalin 2 is a novel regulator of angiogenesis in human breast cancer. FASEB J27: 45-50

107 Yildirim A, Meral M, Kaynar H, Polat H, Ucar EY (2007) Relationship between serum levels of some acute-phase proteins and stage of disease and performance status in patients with lung cancer. Med Sci Monit13: CR195-200

108 Yu Y, Wong J, Lovejoy DB, Kalinowski DS, Richardson DR (2006) Chelators at the cancer coalface: desferrioxamine to Triapine and beyond. Clin Cancer Res12: 6876-6883

109 Zhang C (2014) Essential functions of iron-requiring proteins in DNA replication, repair and cell cycle control. Protein Cell5: 750-760

110 Zhang F, Wang W, Tsuji Y, Torti SV, Torti FM (2008) Posttranscriptional modulation of iron homeostasis during p53-dependent growth arrest. J Biol Chem283: 33911-33918

111 Zhang F, Tao Y, Zhang Z, Guo X, An P, Shen Y, Wu Q, Yu Y, Wang F (2012) Metalloreductase Steap3 coordinates the regulation of iron homeostasis and inflammatory responses. Haematologica97: 1826-1835

112 Zhang C, Liu G, Huang M (2014) Ribonucleotide reductase metallocofactor: assembly, maintenance and inhibition. Front Biol (Beijing)9: 104-113

113 Zhao N, Gao J, Enns CA, Knutson MD (2010) ZRT/IRT-like protein 14 (ZIP14) promotes the cellular assimilation of iron from transferrin. J Biol Chem285: 32141-32150