Zinc Signaling and Cancer

  • Thirayost Nimmanon
  • Kathryn M. TaylorEmail author


The intracellular level of zinc is tightly controlled by ZnT (SLC30A) and ZIP (SLC39A) zinc transport proteins, as well as zinc-binding proteins such as metallothioneins. The ZIP channels are responsible for zinc influx into the cytoplasm, either from the extracellular space or intracellular storage compartments, such as the endoplasmic reticulum and the Golgi, whereas the ZnT transporters transport zinc in the opposite direction. Malfunctions of some zinc transport proteins, resulting in cellular zinc dyshomeostasis and subsequent effects on zinc signaling pathways, have been associated with cancer in a tissue-specific manner. In this chapter we detail what is known about the association between zinc channel and transporter dysregulations and the impact that this has on zinc signaling in different cancers. A particular emphasis is placed on the types of cancer in which the role of zinc dyshomeostasis on carcinogenesis or cancer progression has been most thoroughly investigated, including cancers of the breast, prostate, liver, pancreas, and colorectum. Posttranslational modification by phosphorylation as a novel regulatory mechanism of ZIP channels is also discussed as an important mechanism that may provide a clinical biomarker or target mechanism.


Cancer SLC30A SLC39A Zinc channel Zinc transport ZIP6 ZIP7 


  1. Age-Related Eye Disease Study Research Group (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS Report No. 8. Arch Ophthalmol 119(10):1417–1436. doi: 10.1001/archopht.119.10.1417 PubMedCentralGoogle Scholar
  2. Amaravadi R, Thompson CB (2005) The survival kinases Akt and Pim as potential pharmacological targets. J Clin Invest 115:2618–2624PubMedPubMedCentralGoogle Scholar
  3. Andreini C, Banci L, Bertini I, Rosato A (2006) Counting the zinc-proteins encoded in the human genome. J Proteome Res 5:196–201PubMedGoogle Scholar
  4. Andres SA, Brock GN, Wittliff JL (2013) Interrogating differences in expression of targeted gene sets to predict breast cancer outcome. BMC Cancer 13:326PubMedPubMedCentralGoogle Scholar
  5. Arinola OG, Charles-Davies MA (2008) Micronutrient levels in the plasma of Nigerian females with breast cancer. Afr J Biotechnol 7:1620–1623Google Scholar
  6. Beck FW, Prasad AS, Butler CE, Sakr WA, Kucuk O, Sarkar FH (2004) Differential expression of hZnT-4 in human prostate tissues. Prostate 58:374–381PubMedGoogle Scholar
  7. Bin BH, Fukada T, Hosaka T, Yamasaki S, Ohashi W, Hojyo S, Miyai T, Nishida K, Yokoyama S, Hirano T (2011) Biochemical characterization of human ZIP13 protein: a homo-dimerized zinc transporter involved in the spondylocheiro dysplastic Ehlers–Danlos syndrome. J Biol Chem 286:40255–40265PubMedPubMedCentralGoogle Scholar
  8. Bliesath J, Huser N, Omori M, Bunag D, Proffitt C, Streiner N, Ho C, Siddiqui-Jain A, O’Brien SE, Lim JK et al (2012) Combined inhibition of EGFR and CK2 augments the attenuation of PI3K-Akt-mTOR signaling and the killing of cancer cells. Cancer Lett 322:113–118PubMedGoogle Scholar
  9. Bourdeau A, Dube N, Tremblay ML (2005) Cytoplasmic protein tyrosine phosphatases, regulation and function: the roles of PTP1B and TC-PTP. Curr Opin Cell Biol 17:203–209PubMedGoogle Scholar
  10. Boz A, Evliyaoglu O, Yildirim M, Erkan N, Karaca B (2005) The value of serum zinc, copper, ceruloplasmin levels in patients with gastrointestinal tract cancers. Turk J Gastroenterol 16:81–84PubMedGoogle Scholar
  11. Buntzel J, Bruns F, Glatzel M, Garayev A, Mucke R, Kisters K, Schafer U, Schonekaes K, Micke O (2007) Zinc concentrations in serum during head and neck cancer progression. Anticancer Res 27:1941–1943PubMedGoogle Scholar
  12. Chang ET, Hedelin M, Adami HO, Gronberg H, Balter KA (2004) Re: Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 96:1108, author reply 1108–1109PubMedGoogle Scholar
  13. Chen QG (2012) The role of zinc transporter ZIP4 in prostate carcinoma. Urol Oncol 30:906–911PubMedGoogle Scholar
  14. Chen WW, Chan DC, Donald C, Lilly MB, Kraft AS (2005) Pim family kinases enhance tumor growth of prostate cancer cells. Mol Cancer Res 3:443–451PubMedGoogle Scholar
  15. Colvin RA, Holmes WR, Fontaine CP, Maret W (2010) Cytosolic zinc buffering and muffling: their role in intracellular zinc homeostasis. Metallomics 2:306–317PubMedGoogle Scholar
  16. Costello LC, Franklin RB (2006) The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol Cancer 5:17PubMedPubMedCentralGoogle Scholar
  17. Costello LC, Franklin RB (2013). A review of the current status and concept of the emerging implications of zinc and zinc transporters in the development of pancreatic cancer. Pancreat Disord Ther Suppl 4:002Google Scholar
  18. Costello LC, Liu Y, Franklin RB, Kennedy MC (1997) Zinc inhibition of mitochondrial aconitase and its importance in citrate metabolism of prostate epithelial cells. J Biol Chem 272:28875–28881PubMedGoogle Scholar
  19. Costello LC, Franklin RB, Feng P, Tan M, Bagasra O (2005) Zinc and prostate cancer: a critical scientific, medical, and public interest issue (United States). Cancer Causes Control 16:901–915PubMedGoogle Scholar
  20. Costello LC, Levy BA, Desouki MM, Zou J, Bagasra O, Johnson LA, Hanna N, Franklin RB (2011) Decreased zinc and downregulation of ZIP3 zinc uptake transporter in the development of pancreatic adenocarcinoma. Cancer Biol Ther 12:297–303PubMedPubMedCentralGoogle Scholar
  21. Costello LC, Zou J, Desouki MM, Franklin RB (2012) Evidence for changes in RREB-1, ZIP3, and zinc in the early development of pancreatic adenocarcinoma. J Gastrointest Cancer 43:570–578PubMedPubMedCentralGoogle Scholar
  22. Cousins RJ, Liuzzi JP, Lichten LA (2006) Mammalian zinc transport, trafficking, and signals. J Biol Chem 281:24085–24089PubMedGoogle Scholar
  23. Cui Y, Vogt S, Olson N, Glass AG, Rohan TE (2007) Levels of zinc, selenium, calcium, and iron in benign breast tissue and risk of subsequent breast cancer. Cancer Epidemiol Biomarkers Prev 16:1682–1685PubMedGoogle Scholar
  24. Dani V, Goel A, Vaiphei K, Dhawan DK (2007) Chemopreventive potential of zinc in experimentally induced colon carcinogenesis. Toxicol Lett 171:10–18PubMedGoogle Scholar
  25. Daub H, Olsen JV, Bairlein M, Gnad F, Oppermann FS, Korner R, Greff Z, Keri G, Stemmann O, Mann M (2008) Kinase-selective enrichment enables quantitative phosphoproteomics of the kinome across the cell cycle. Mol Cell 31:438–448PubMedGoogle Scholar
  26. Desouki MM, Geradts J, Milon B, Franklin RB, Costello LC (2007) hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol Cancer 6:37PubMedPubMedCentralGoogle Scholar
  27. Dhawan DK, Chadha VD (2010) Zinc: a promising agent in dietary chemoprevention of cancer. Indian J Med Res 132:676–682PubMedPubMedCentralGoogle Scholar
  28. Duncan JS, Litchfield DW (2008) Too much of a good thing: the role of protein kinase CK2 in tumorigenesis and prospects for therapeutic inhibition of CK2. Biochim Biophys Acta 1784:33–47PubMedGoogle Scholar
  29. Ehsani S, Salehzadeh A, Huo H, Reginold W, Pocanschi CL, Ren H, Wang H, So K, Sato C, Mehrabian M et al (2012) LIV-1 ZIP ectodomain shedding in prion-infected mice resembles cellular response to transition metal starvation. J Mol Biol 422:556–574PubMedGoogle Scholar
  30. Eide DJ (2004) The SLC39 family of metal ion transporters. Pflugers Arch 447:796–800PubMedGoogle Scholar
  31. Feng P, Li TL, Guan ZX, Franklin RB, Costello LC (2002) Direct effect of zinc on mitochondrial apoptogenesis in prostate cells. Prostate 52:311–318PubMedGoogle Scholar
  32. Feng P, Li T, Guan Z, Franklin RB, Costello LC (2008) The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells. Mol Cancer 7:25PubMedPubMedCentralGoogle Scholar
  33. Food and Nutrition Board of Institute of Medicine (2001) Zinc. In: Dietary Reference Intakes for Vitamin A, Vitamin K, Arsenic, Boron, Chromium, Copper, Iodine, Iron, Manganese, Molybdenum, Nickel, Silicon, Vanadium, and Zinc. National Academy Press, Washington, D.C., pp 442–501Google Scholar
  34. Fong LY, Nguyen VT, Farber JL (2001) Esophageal cancer prevention in zinc-deficient rats: rapid induction of apoptosis by replenishing zinc. J Natl Cancer Inst 93:1525–1533PubMedGoogle Scholar
  35. Fraker PJ (2005) Roles for cell death in zinc deficiency. J Nutr 135:359–362PubMedGoogle Scholar
  36. Franklin RB, Costello LC (2007) Zinc as an anti-tumor agent in prostate cancer and in other cancers. Arch Biochem Biophys 463:211–217PubMedPubMedCentralGoogle Scholar
  37. Franklin RB, Feng P, Milon B, Desouki MM, Singh KK, Kajdacsy-Balla A, Bagasra O, Costello LC (2005) hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol Cancer 4:32PubMedPubMedCentralGoogle Scholar
  38. Franklin RB, Levy BA, Zou J, Hanna N, Desouki MM, Bagasra O, Johnson LA, Costello LC (2012) ZIP14 zinc transporter downregulation and zinc depletion in the development and progression of hepatocellular cancer. J Gastrointest Cancer 43:249–257PubMedPubMedCentralGoogle Scholar
  39. Fukada T, Kambe T (2011) Molecular and genetic features of zinc transporters in physiology and pathogenesis. Metallomics 3:662–674PubMedGoogle Scholar
  40. Gnad F, Ren S, Cox J, Olsen JV, Macek B, Oroshi M, Mann M (2007) PHOSIDA (phosphorylation site database): management, structural and evolutionary investigation, and prediction of phosphosites. Genome Biol 8:R250PubMedPubMedCentralGoogle Scholar
  41. Gupta SK, Singh SP, Shukla VK (2005) Copper, zinc, and Cu/Zn ratio in carcinoma of the gallbladder. J Surg Oncol 91:204–208PubMedGoogle Scholar
  42. Haase H, Maret W (2005) Protein tyrosine phosphatases as targets of the combined insulinomimetic effects of zinc and oxidants. Biometals 18:333–338PubMedGoogle Scholar
  43. Hambidge KM, Krebs NF (2007) Zinc deficiency: a special challenge. J Nutr 137:1101–1105PubMedGoogle Scholar
  44. Hasumi M, Suzuki K, Matsui H, Koike H, Ito K, Yamanaka H (2003) Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues. Cancer Lett 200:187–195PubMedGoogle Scholar
  45. Hiscox S, Morgan L, Barrow D, Dutkowskil C, Wakeling A, Nicholson RI (2004) Tamoxifen resistance in breast cancer cells is accompanied by an enhanced motile and invasive phenotype: inhibition by gefitinib (‘Iressa’, ZD1839). Clin Exp Metastasis 21:201–212PubMedGoogle Scholar
  46. Hiscox S, Morgan L, Green TP, Barrow D, Gee J, Nicholson RI (2006) Elevated Src activity promotes cellular invasion and motility in tamoxifen resistant breast cancer cells. Breast Cancer Res Treat 97:263–274PubMedGoogle Scholar
  47. Ho E (2004) Zinc deficiency, DNA damage and cancer risk. J Nutr Biochem 15:572–578PubMedGoogle Scholar
  48. Ho E, Ames BN (2002) Low intracellular zinc induces oxidative DNA damage, disrupts p53, NFkappa B, and AP1 DNA binding, and affects DNA repair in a rat glioma cell line. Proc Natl Acad Sci USA 99:16770–16775PubMedPubMedCentralGoogle Scholar
  49. Ho E, Courtemanche C, Ames BN (2003) Zinc deficiency induces oxidative DNA damage and increases p53 expression in human lung fibroblasts. J Nutr 133:2543–2548PubMedGoogle Scholar
  50. Hogstrand C, Kille P, Nicholson RI, Taylor KM (2009) Zinc transporters and cancer: a potential role for ZIP7 as a hub for tyrosine kinase activation. Trends Mol Med 15:101–111PubMedGoogle Scholar
  51. Hogstrand C, Kille P, Ackland ML, Hiscox S, Taylor KM (2013) A mechanism for epithelial-mesenchymal transition and anoikis resistance in breast cancer triggered by zinc channel ZIP6 and STAT3 (signal transducer and activator of transcription 3). Biochem J 455:229–237PubMedPubMedCentralGoogle Scholar
  52. Hornbeck PV, Kornhauser JM, Tkachev S, Zhang B, Skrzypek E, Murray B, Latham V, Sullivan M (2012) PhosphoSitePlus: a comprehensive resource for investigating the structure and function of experimentally determined post-translational modifications in man and mouse. Nucleic Acids Res 40:D261–D270PubMedPubMedCentralGoogle Scholar
  53. Huang L, Tepaamorndech S (2013) The SLC30 family of zinc transporters: a review of current understanding of their biological and pathophysiological roles. Mol Aspects Med 34:548–560PubMedGoogle Scholar
  54. Huang L, Kirschke CP, Zhang Y, Yu YY (2005) The ZIP7 gene (Slc39a7) encodes a zinc transporter involved in zinc homeostasis of the Golgi apparatus. J Biol Chem 280:15456–15463PubMedGoogle Scholar
  55. Huang L, Kirschke CP, Zhang Y (2006) Decreased intracellular zinc in human tumorigenic prostate epithelial cells: a possible role in prostate cancer progression. Cancer Cell Int 6:10PubMedPubMedCentralGoogle Scholar
  56. Ilouz R, Kaidanovich O, Gurwitz D, Eldar-Finkelman H (2002) Inhibition of glycogen synthase kinase-3beta by bivalent zinc ions: insight into the insulin-mimetic action of zinc. Biochem Biophys Res Commun 295:102–106PubMedGoogle Scholar
  57. Jin R, Bay B, Tan P, Tan BK (1999) Metallothionein expression and zinc levels in invasive ductal breast carcinoma. Oncol Rep 6:871–875PubMedGoogle Scholar
  58. John E, Laskow TC, Buchser WJ, Pitt BR, Basse PH, Butterfield LH, Kalinski P, Lotze MT (2010) Zinc in innate and adaptive tumor immunity. J Transl Med 8:118PubMedPubMedCentralGoogle Scholar
  59. Jones HE, Goddard L, Gee JM, Hiscox S, Rubini M, Barrow D, Knowlden JM, Williams S, Wakeling AE, Nicholson RI (2004) Insulin-like growth factor-I receptor signalling and acquired resistance to gefitinib (ZD1839; Iressa) in human breast and prostate cancer cells. Endocr Relat Cancer 11:793–814PubMedGoogle Scholar
  60. Kagara N, Tanaka N, Noguchi S, Hirano T (2007) Zinc and its transporter ZIP10 are involved in invasive behavior of breast cancer cells. Cancer Sci 98:692–697PubMedGoogle Scholar
  61. Kambe T, Suzuki T, Nagao M, Yamaguchi-Iwai Y (2006) Sequence similarity and functional relationship among eukaryotic ZIP and CDF transporters. Genomics Proteomics Bioinformatics 4:1–9PubMedGoogle Scholar
  62. Kasper G, Weiser AA, Rump A, Sparbier K, Dahl E, Hartmann A, Wild P, Schwidetzky U, Castanos-Velez E, Lehmann K (2005) Expression levels of the putative zinc transporter LIV-1 are associated with a better outcome of breast cancer patients. Int J Cancer 117:961–973PubMedGoogle Scholar
  63. Kelleher SL, McCormick NH, Velasquez V, Lopez V (2011) Zinc in specialized secretory tissues: roles in the pancreas, prostate, and mammary gland. Adv Nutr 2:101–111PubMedPubMedCentralGoogle Scholar
  64. Kim YH, Kim EY, Gwag BJ, Sohn S, Koh JY (1999) Zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals. Neuroscience 89:175–182PubMedGoogle Scholar
  65. Kim JE, Tannenbaum SR, White FM (2005) Global phosphoproteome of HT-29 human colon adenocarcinoma cells. J Proteome Res 4:1339–1346PubMedGoogle Scholar
  66. Knowlden JM, Hutcheson IR, Jones HE, Madden T, Gee JM, Harper ME, Barrow D, Wakeling AE, Nicholson RI (2003) Elevated levels of epidermal growth factor receptor/c-erbB2 heterodimers mediate an autocrine growth regulatory pathway in tamoxifen-resistant MCF-7 cells. Endocrinology 144:1032–1044PubMedGoogle Scholar
  67. Kolonel LN, Yoshizawa CN, Hankin JH (1988) Diet and prostatic cancer: a case-control study in Hawaii. Am J Epidemiol 127:999–1012PubMedGoogle Scholar
  68. Kristal AR, Stanford JL, Cohen JH, Wicklund K, Patterson RE (1999) Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol Biomarkers Prev 8:887–892PubMedGoogle Scholar
  69. Krone CA, Harms LC (2003) Re: Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 95:1556–1557PubMedGoogle Scholar
  70. Lansdown AB, Mirastschijski U, Stubbs N, Scanlon E, Agren MS (2007) Zinc in wound healing: theoretical, experimental, and clinical aspects. Wound Repair Regen 15:2–16PubMedGoogle Scholar
  71. Lee R, Woo W, Wu B, Kummer A, Duminy H, Xu Z (2003) Zinc accumulation in N-methyl-N-nitrosourea-induced rat mammary tumors is accompanied by an altered expression of ZnT-1 and metallothionein. Exp Biol Med 228:689–696Google Scholar
  72. Lee S, Chanoit G, McIntosh R, Zvara DA, Xu Z (2009) Molecular mechanism underlying Akt activation in zinc-induced cardioprotection. Am J Physiol 297:H569–H575Google Scholar
  73. Leitzmann MF (2003) Zinc supplement use and risk of prostate cancer. J Natl Cancer Inst 95:1004–1007PubMedGoogle Scholar
  74. Lester SC (2010) The breast. In: Kumar V, Abbas AK, Fausto N, Aster JC (eds) Robbins and Cotran pathologic basis of disease, 8th edn. Saunders Elsevier, PhiladelphiaGoogle Scholar
  75. Li M, Zhang Y, Liu Z, Bharadwaj U, Wang H, Wang X, Zhang S, Liuzzi JP, Chang SM, Cousins RJ et al (2007) Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression. Proc Natl Acad Sci USA 104:18636–18641PubMedPubMedCentralGoogle Scholar
  76. Lichten LA, Cousins RJ (2009) Mammalian zinc transporters: nutritional and physiologic regulation. Annu Rev Nutr 29:153–176PubMedGoogle Scholar
  77. Lu M, Fu D (2007) Structure of the zinc transporter YiiP. Science 317:1746–1748PubMedGoogle Scholar
  78. MacDonald RS (2000) The role of zinc in growth and cell proliferation. J Nutr 130:1500S–1508SPubMedGoogle Scholar
  79. Manning DL, McClelland RA, Gee JM, Chan CM, Green CD, Blamey RW, Nicholson RI (1993) The role of four oestrogen-responsive genes, pLIV1, pS2, pSYD3 and pSYD8, in predicting responsiveness to endocrine therapy in primary breast cancer. Eur J Cancer 29A:1462–1468PubMedGoogle Scholar
  80. Manning DL, Robertson JF, Ellis IO, Elston CW, McClelland RA, Gee JM, Jones RJ, Green CD, Cannon P, Blamey RW et al (1994) Oestrogen-regulated genes in breast cancer: association of pLIV1 with lymph node involvement. Eur J Cancer 30A:675–678PubMedGoogle Scholar
  81. Maret W (2001) Zinc biochemistry, physiology, and homeostasis: recent insights and current trends. Biometals 14:187–190Google Scholar
  82. Margalioth EJ, Schenker JG, Chevion M (1983) Copper and zinc levels in normal and malignant tissues. Cancer (Phila) 52:868–872Google Scholar
  83. Martin-Lagos F, Navarro-Alarcon M, Terres-Martos C, López-G de la Serrana H, Lopez-Martinez MC (1997) Serum copper and zinc concentrations in serum from patients with cancer and cardiovascular disease. Sci Total Environ 204:27–35PubMedGoogle Scholar
  84. Martins LR, Lucio P, Melao A, Antunes I, Cardoso BA, Stansfield R, Bertilaccio MT, Ghia P, Drygin D, Silva MG et al (2013) Activity of the clinical-stage CK2-specific inhibitor CX-4945 against chronic lymphocytic leukemia. Leukemia 28:179–182PubMedGoogle Scholar
  85. Matsuura W, Yamazaki T, Yamaguchi-Iwai Y, Masuda S, Nagao M, Andrews GK, Kambe T (2009) SLC39A9 (ZIP9) regulates zinc homeostasis in the secretory pathway: characterization of the ZIP subfamily I protein in vertebrate cells. Biosci Biotechnol Biochem 73:1142–1148PubMedGoogle Scholar
  86. Memon AU, Kazi TG, Afridi HI, Jamali MK, Arain MB, Jalbani N, Syed N (2007) Evaluation of zinc status in whole blood and scalp hair of female cancer patients. Clin Chim Acta 379:66–70PubMedGoogle Scholar
  87. Menon MB, Ronkina N, Schwermann J, Kotlyarov A, Gaestel M (2009) Fluorescence-based quantitative scratch wound healing assay demonstrating the role of MAPKAPK-2/3 in fibroblast migration. Cell Motil Cytoskeleton 66:1041–1047PubMedGoogle Scholar
  88. Miura K, Fujibuchi W, Unno M (2012) Splice isoforms as therapeutic targets for colorectal cancer. Carcinogenesis (Oxf) 33:2311–2319Google Scholar
  89. Mulay IL, Roy R, Knox BE, Suhr NH, Delaney WE (1971) Trace-metal analysis of cancerous and noncancerous human tissues. J Natl Cancer Inst 47:1–13PubMedGoogle Scholar
  90. Naidu MS, Suryakar AN, Swami SC, Katkam RV, Kumbar KM (2007) Oxidative stress and antioxidant status in cervical cancer patients. Indian J Clin Biochem 22:140–144PubMedPubMedCentralGoogle Scholar
  91. Navarro Silvera SA, Rohan TE (2007) Trace elements and cancer risk: a review of the epidemiologic evidence. Cancer Causes Control 18:7–27PubMedGoogle Scholar
  92. Niefind K, Raaf J, Issinger OG (2009) Protein kinase CK2 in health and disease: protein kinase CK2: from structures to insights. Cell Mol Life Sci 66:1800–1816PubMedGoogle Scholar
  93. Ohana E, Hoch E, Keasar C, Kambe T, Yifrach O, Hershfinkel M, Sekler I (2009) Identification of the Zn2+ binding site and mode of operation of a mammalian Zn2+ transporter. J Biol Chem 284:17677–17686PubMedPubMedCentralGoogle Scholar
  94. Olsen JV, Vermeulen M, Santamaria A, Kumar C, Miller ML, Jensen LJ, Gnad F, Cox J, Jensen TS, Nigg EA et al (2010) Quantitative phosphoproteomics reveals widespread full phosphorylation site occupancy during mitosis. Sci Signal 3:ra3PubMedGoogle Scholar
  95. Osborne CK (1998) Tamoxifen in the treatment of breast cancer. N Engl J Med 339:1609–1618PubMedGoogle Scholar
  96. Oteiza PI (2012) Zinc and the modulation of redox homeostasis. Free Radic Biol Med 53:1748–1759PubMedPubMedCentralGoogle Scholar
  97. Pakala SB, Rayala SK, Wang RA, Ohshiro K, Mudvari P, Reddy SD, Zheng Y, Pires R, Casimiro S, Pillai MR et al (2013) MTA1 promotes STAT3 transcription and pulmonary metastasis in breast cancer. Cancer Res 73:3761–3770PubMedPubMedCentralGoogle Scholar
  98. Palmiter RD, Findley SD (1995) Cloning and functional characterization of a mammalian zinc transporter that confers resistance to zinc. EMBO J 14:639–649PubMedPubMedCentralGoogle Scholar
  99. Passerini A, Andreini C, Menchetti S, Rosato A, Frasconi P (2007) Predicting zinc binding at the proteome level. BMC Bioinformatics 8:39PubMedPubMedCentralGoogle Scholar
  100. Peinado H, Olmeda D, Cano A (2007) Snail, Zeb and bHLH factors in tumour progression: an alliance against the epithelial phenotype? Nat Rev Cancer 7:415–428PubMedGoogle Scholar
  101. Perou CM, Sorlie T, Eisen MB, van de Rijn M, Jeffrey SS, Rees CA, Pollack JR, Ross DT, Johnsen H, Akslen LA et al (2000) Molecular portraits of human breast tumours. Nature (Lond) 406:747–752Google Scholar
  102. Piccinini L, Borella P, Bargellini A, Medici CI, Zoboli A (1996) A case-control study on selenium, zinc, and copper in plasma and hair of subjects affected by breast and lung cancer. Biol Trace Elem Res 51:23–30PubMedGoogle Scholar
  103. Plum LM, Rink L, Haase H (2010) The essential toxin: impact of zinc on human health. Int J Environ Res Public Health 7:1342–1365PubMedPubMedCentralGoogle Scholar
  104. Prasad AS (2009) Impact of the discovery of human zinc deficiency on health. J Am Coll Nutr 28:257–265PubMedGoogle Scholar
  105. Prasad AS, Beck FW, Snell DC, Kucuk O (2009) Zinc in cancer prevention. Nutr Cancer 61:879–887PubMedGoogle Scholar
  106. Ring A, Dowsett M (2004) Mechanisms of tamoxifen resistance. Endocr Relat Cancer 11:643–658PubMedGoogle Scholar
  107. Satoh M, Kondo Y, Mita M, Nakagawa I, Naganuma A, Imura N (1993) Prevention of carcinogenicity of anticancer drugs by metallothionein induction. Cancer Res 53:4767–4768PubMedGoogle Scholar
  108. Science M, Johnstone J, Roth DE, Guyatt G, Loeb M (2012) Zinc for the treatment of the common cold: a systematic review and meta-analysis of randomized controlled trials. Can Med Assoc J 184:E551–E561Google Scholar
  109. Seve M, Chimienti F, Devergnas S, Favier A (2004) In silico identification and expression of SLC30 family genes: an expressed sequence tag data mining strategy for the characterization of zinc transporters’ tissue expression. BMC Genomics 5:32PubMedPubMedCentralGoogle Scholar
  110. Shen R, Xie F, Shen H, Liu Q, Zheng T, Kou X, Wang D, Yang J (2013) Negative correlation of LIV-1 and E-cadherin expression in hepatocellular carcinoma cells. PLoS One 8:e56542PubMedPubMedCentralGoogle Scholar
  111. Siddiqui-Jain A, Drygin D, Streiner N, Chua P, Pierre F, O’Brien SE, Bliesath J, Omori M, Huser N, Ho C et al (2010) CX-4945, an orally bioavailable selective inhibitor of protein kinase CK2, inhibits prosurvival and angiogenic signaling and exhibits antitumor efficacy. Cancer Res 70:10288–10298PubMedGoogle Scholar
  112. Solares AM, Santana A, Baladron I, Valenzuela C, Gonzalez CA, Diaz A, Castillo D, Ramos T, Gomez R, Alonso DF et al (2009) Safety and preliminary efficacy data of a novel casein kinase 2 (CK2) peptide inhibitor administered intralesionally at four dose levels in patients with cervical malignancies. BMC Cancer 9:146PubMedPubMedCentralGoogle Scholar
  113. St.-Denis NA, Litchfield DW (2009) Protein kinase CK2 in health and disease: from birth to death: the role of protein kinase CK2 in the regulation of cell proliferation and survival. Cell Mol Life Sci 66:1817–1829PubMedGoogle Scholar
  114. Summy JM, Gallick GE (2006) Treatment for advanced tumors: SRC reclaims center stage. Clin Cancer Res 12:1398–1401PubMedGoogle Scholar
  115. Sussman D, Smith LM, Anderson ME, Duniho S, Hunter JH, Kostner H, Miyamoto JB, Nesterova A, Westendorf L, Van Epps HA et al (2013) SGN-LIV1A: a development stage antibody drug-conjugate targeting LIV-1 for the treatment of metastatic breast cancer. Cancer Res 73(abstr 3962)Google Scholar
  116. Sveen A, Bakken AC, Agesen TH, Lind GE, Nesbakken A, Nordgard O, Brackmann S, Rognum TO, Lothe RA, Skotheim RI (2012) The exon-level biomarker SLC39A14 has organ-confined cancer-specificity in colorectal cancer. Int J Cancer 131:1479–1485PubMedGoogle Scholar
  117. Swinkels JW, Kornegay ET, Verstegen MW (1994) Biology of zinc and biological value of dietary organic zinc complexes and chelates. Nutr Res Rev 7:129–149PubMedGoogle Scholar
  118. Taniguchi M, Fukunaka A, Hagihara M, Watanabe K, Kamino S, Kambe T, Enomoto S, Hiromura M (2013) Essential role of the zinc transporter ZIP9/SLC39A9 in regulating the activations of Akt and Erk in B-cell receptor signaling pathway in DT40 cells. PLoS One 8:e58022PubMedPubMedCentralGoogle Scholar
  119. Tawfic S, Yu S, Wang H, Faust R, Davis A, Ahmed K (2001) Protein kinase CK2 signal in neoplasia. Histol Histopathol 16:573–582PubMedGoogle Scholar
  120. Taylor KM, Nicholson RI (2003) The LZT proteins: the LIV-1 subfamily of zinc transporters. Biochim Biophys Acta 1611:16–30PubMedGoogle Scholar
  121. Taylor KM, Morgan HE, Johnson A, Hadley LJ, Nicholson RI (2003) Structure–function analysis of LIV-1, the breast cancer-associated protein that belongs to a new subfamily of zinc transporters. Biochem J 375:51–59PubMedPubMedCentralGoogle Scholar
  122. Taylor KM, Morgan HE, Johnson A, Nicholson RI (2004) Structure–function analysis of HKE4, a member of the new LIV-1 subfamily of zinc transporters. Biochem J 377:131–139PubMedPubMedCentralGoogle Scholar
  123. Taylor KM, Morgan HE, Smart K, Zahari NM, Pumford S, Ellis IO, Robertson JF, Nicholson RI (2007) The emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol Med 13:396–406PubMedPubMedCentralGoogle Scholar
  124. Taylor KM, Vichova P, Jordan N, Hiscox S, Hendley R, Nicholson RI (2008) ZIP7-mediated intracellular zinc transport contributes to aberrant growth factor signaling in antihormone-resistant breast cancer Cells. Endocrinology 149:4912–4920PubMedGoogle Scholar
  125. Taylor KM, Gee JMW, Kille P (2011) Zinc and cancer. In: Rink L (ed) Zinc in human health. IOS Press, Amsterdam, pp 283–304Google Scholar
  126. Taylor KM, Hiscox S, Nicholson RI, Hogstrand C, Kille P (2012a) Protein kinase CK2 triggers cytosolic zinc signaling pathways by phosphorylation of zinc channel ZIP7. Sci Signal 5:ra11PubMedPubMedCentralGoogle Scholar
  127. Taylor KM, Kille P, Hogstrand C (2012b) Protein kinase CK2 opens the gate for zinc signaling. Cell Cycle 11Google Scholar
  128. Thiery JP, Acloque H, Huang RY, Nieto MA (2009) Epithelial-mesenchymal transitions in development and disease. Cell 139:871–890PubMedGoogle Scholar
  129. Thorsen K, Mansilla F, Schepeler T, Oster B, Rasmussen MH, Dyrskjot L, Karni R, Akerman M, Krainer AR, Laurberg S et al (2011) Alternative splicing of SLC39A14 in colorectal cancer is regulated by the Wnt pathway. Mol Cell Proteomics 10(M110):002998PubMedGoogle Scholar
  130. Tozlu S, Girault I, Vacher S, Vendrell J, Andrieu C, Spyratos F, Cohen P, Lidereau R, Bieche I (2006) Identification of novel genes that co-cluster with estrogen receptor alpha in breast tumor biopsy specimens, using a large-scale real-time reverse transcription-PCR approach. Endocr Relat Cancer 13:1109–1120PubMedGoogle Scholar
  131. Walker CL, Black RE (2010) Zinc for the treatment of diarrhoea: effect on diarrhoea morbidity, mortality and incidence of future episodes. Int J Epidemiol 39(Suppl 1):i63–i69PubMedPubMedCentralGoogle Scholar
  132. Wang SS, Sherman ME, Hildesheim A, Lacey JV Jr, Devesa S (2004) Cervical adenocarcinoma and squamous cell carcinoma incidence trends among white women and black women in the United States for 1976–2000. Cancer (Phila) 100:1035–1044Google Scholar
  133. Weaver BP, Zhang Y, Hiscox S, Guo GL, Apte U, Taylor KM, Sheline CT, Wang L, Andrews GK (2010) Zip4 (Slc39a4) expression is activated in hepatocellular carcinomas and functions to repress apoptosis, enhance cell cycle and increase migration. PLoS One 5Google Scholar
  134. Welsch CW (1985) Host factors affecting the growth of carcinogen-induced rat mammary carcinomas: a review and tribute to Charles Brenton Huggins. Cancer Res 45:3415–3443PubMedGoogle Scholar
  135. Woo W, Xu Z (2002) Body zinc distribution profile during N-methyl-N-nitrosourea-induced mammary tumorigenesis in rats at various levels of dietary zinc intake. Biol Trace Elem Res 87:157–169PubMedGoogle Scholar
  136. World Health Organization and Food and Agriculture Organization of The United Nations (2002) Zinc. In: FAO/WHO expert consultation on human vitamin and mineral requirements. Rome, pp 257–270Google Scholar
  137. Yamasaki S, Sakata-Sogawa K, Hasegawa A, Suzuki T, Kabu K, Sato E, Kurosaki T, Yamashita S, Tokunaga M, Nishida K et al (2007) Zinc is a novel intracellular second messenger. J Cell Biol 177:637–645PubMedPubMedCentralGoogle Scholar
  138. Yamashita S, Miyagi C, Fukada T, Kagara N, Che YS, Hirano T (2004) Zinc transporter LIVI controls epithelial-mesenchymal transition in zebrafish gastrula organizer. Nature (Lond) 429:298–302Google Scholar
  139. Yan M, Song Y, Wong CP, Hardin K, Ho E (2008) Zinc deficiency alters DNA damage response genes in normal human prostate epithelial cells. J Nutr 138:667–673PubMedPubMedCentralGoogle Scholar
  140. Yang J, Zhang Y, Cui X, Yao W, Yu X, Cen P, Hodges SE, Fisher WE, Brunicardi FC, Chen C et al (2013) Gene profile identifies zinc transporters differentially expressed in normal human organs and human pancreatic cancer. Curr Mol Med 13:401–409PubMedPubMedCentralGoogle Scholar
  141. Yde CW, Frogne T, Lykkesfeldt AE, Fichtner I, Issinger OG, Stenvang J (2007) Induction of cell death in antiestrogen resistant human breast cancer cells by the protein kinase CK2 inhibitor DMAT. Cancer Lett 256:229–237PubMedGoogle Scholar
  142. Yoshida K, Kawano N, Yoshiike M, Yoshida M, Iwamoto T, Morisawa M (2008) Physiological roles of semenogelin I and zinc in sperm motility and semen coagulation on ejaculation in humans. Mol Hum Reprod 14:151–156PubMedGoogle Scholar
  143. Yu M, Lee WW, Tomar D, Pryshchep S, Czesnikiewicz-Guzik M, Lamar DL, Li G, Singh K, Tian L, Weyand CM et al (2011) Regulation of T cell receptor signaling by activation-induced zinc influx. J Exp Med 208:775–785PubMedPubMedCentralGoogle Scholar
  144. Zahedi RP, Lewandrowski U, Wiesner J, Wortelkamp S, Moebius J, Schutz C, Walter U, Gambaryan S, Sickmann A (2008) Phosphoproteome of resting human platelets. J Proteome Res 7:526–534PubMedGoogle Scholar
  145. Zaichick V, Sviridova TV, Zaichick SV (1997) Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int Urol Nephrol 29:565–574PubMedGoogle Scholar
  146. Zhang Y, Bharadwaj U, Logsdon CD, Chen C, Yao Q, Li M (2010) ZIP4 regulates pancreatic cancer cell growth by activating IL-6/STAT3 pathway through zinc finger transcription factor CREB. Clin Cancer Res 16:1423–1430PubMedPubMedCentralGoogle Scholar
  147. Zhang A, Wang Q, Han Z, Hu W, Xi L, Gao Q, Wang S, Zhou J, Xu G, Meng L et al (2013) Reduced expression of Snail decreases breast cancer cell motility by downregulating the expression and inhibiting the activity of RhoA GTPase. Oncol Lett 6:339–346PubMedPubMedCentralGoogle Scholar
  148. Zheng Y, McFarland BC, Drygin D, Yu H, Bellis SL, Kim H, Bredel M, Benveniste EN (2013) Targeting protein kinase CK2 suppresses prosurvival signaling pathways and growth of glioblastoma. Clin Cancer Res 19(23):6484–6494. doi: 10.1158/1078-0432.CCR-13-0265 PubMedGoogle Scholar
  149. Zhou BP, Deng J, Xia W, Xu J, Li YM, Gunduz M, Hung MC (2004) Dual regulation of snail by GSK-3beta-mediated phosphorylation in control of epithelial-mesenchymal transition. Nat Cell Biol 6:931–940PubMedGoogle Scholar

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© Springer Japan 2014

Authors and Affiliations

  1. 1.Cardiff School of Pharmacy and Pharmaceutical Sciences, Redwood BuildingCardiff UniversityCardiffUK

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