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Zinc and zinc transporters in prostate carcinogenesis

Nature Reviews Urology volume 10, pages 219–226 (2013)Cite this article

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Abstract

The healthy human prostate accumulates the highest level of zinc of any soft tissue in the body. This unique property is retained in BPH, but is lost in prostatic malignancy, which implicates changes in zinc and its transporters in carcinogenesis. Indeed, zinc concentrations diminish early in the course of prostate carcinogenesis, preceding histopathological changes, and continue to decline during progression toward castration-resistant disease. Numerous studies suggest that increased zinc intake might protect against progression of prostatic malignancy. In spite of increased dietary intake, zinc accumulation might be limited by the diminished expression of zinc uptake transporters, resulting in decreased intratumoural zinc levels. This finding can explain the conflicting results of various epidemiological studies evaluating the role of zinc supplementation on primary and secondary prostate cancer prevention. Overall, more research into the mechanisms of zinc homeostasis are needed to fully understand its impact on prostate carcinogenesis. Only then can the potential of zinc and zinc transport proteins be harnessed in the diagnosis and treatment of men with prostate cancer.

Key Points

  • In vitro and in vivo experimental studies have revealed a strong association between prostate cancer and the downregulation of intracellular zinc content

  • To escape the antitumour effects of intracellular zinc, malignant prostate cells can reduce expression of zinc uptake transporters through multiple mechanisms

  • Failure to accumulate zinc via the diminished expression of zinc uptake transporters can, in turn, result in decreased intratumoural zinc levels despite adequate dietary zinc intake

  • This finding can explain the conflicting results of various epidemiological studies evaluating the role of zinc supplementation on primary and secondary prostate cancer prevention

  • The importance of changes in zinc accumulation in prostate carcinogenesis emphasizes the potential roles of zinc and zinc transport proteins for the development of novel diagnostic and therapeutic modalities

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Figure 1: The biological roles of zinc.
Figure 2: The roles of zinc in tumour suppression.
Figure 3: A zinc-mediated shift in the Bax to Bcl-2 ratio promotes the translocation of cytochrome c from the mitochondria to the cytosol, which triggers the activation of caspase 9 and caspase 3, cleavage of nuclear PARP and, ultimately, apoptosis.

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References

  1. Chasapis, C. T., Loutsidou, A. C., Spiliopoulou, C. A. & Stefanidou, M. E. Zinc and human health: an update. Arch. Toxicol. 86, 521–534 (2012).

    Article  CAS  PubMed  Google Scholar 

  2. Rink, L. & Gabriel, P. Zinc and the immune system. Proc. Nutr. Soc. 59, 541–552 (2000).

    Article  CAS  PubMed  Google Scholar 

  3. Trumbo, P., Yates, A. A., Schlicker, S. & Poos, M. Dietary reference intakes: vitamin A, vitamin K, arsenic, boron, chromium, copper, iodine, iron, manganese, molybdenum, nickel, silicon, vanadium, and zinc. J. Am. Diet Assoc. 101, 294–301 (2001).

    Article  CAS  PubMed  Google Scholar 

  4. Costello, L. C., Feng, P., Milon, B., Tan, M. & Franklin, R. B. Role of zinc in the pathogenesis and treatment of prostate cancer: critical issues to resolve. Prostate Cancer Prostatic Dis. 7, 111–117 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Costello, L. C. & Franklin, R. B. The clinical relevance of the metabolism of prostate cancer; zinc and tumor suppression: connecting the dots. Mol. Cancer 5, 17 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Feng, P., Li, T. L., Guan, Z. X., Franklin, R. B. & Costello, L. C. Effect of zinc on prostatic tumorigenicity in nude mice. Ann. NY Acad. Sci. 1010, 316–320 (2003).

    Article  CAS  PubMed  Google Scholar 

  7. Franklin, R. B. & Costello, L. C. Zinc as an anti-tumor agent in prostate cancer and in other cancers. Arch. Biochem. Biophys. 463, 211–217 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Franklin, R. B., Milon, B., Feng, P. & Costello, L. C. Zinc and zinc transporters in normal prostate and the pathogenesis of prostate cancer. Front. Biosci. 10, 2230–2239 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Golovine, K. et al. Overexpression of the zinc uptake transporter hZIP1 inhibits nuclear factor-kappaB and reduces the malignant potential of prostate cancer cells in vitro and in vivo. Clin. Cancer Res. 14, 5376–5384 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Golovine, K. et al. Depletion of intracellular zinc increases expression of tumorigenic cytokines VEGF, IL-6 and IL-8 in prostate cancer cells via NF-kB-dependent pathway. Prostate 68, 1443–1449 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Uzzo, R. G. et al. Zinc Inhibits Nuclear Factor-kappaB Activation and Sensitizes Prostate Cancer Cells to Cytotoxic Agents. Clin. Cancer Res. 8, 3579–3583 (2002).

    CAS  PubMed  Google Scholar 

  12. Chang, E. T., Hedelin, M., Adami, H. O., Grönberg, H. & Bälter, K. A. Re: Zinc supplement use and risk of prostate cancer. J. Natl Cancer Inst. 96, 1108–1109 (2004).

    Article  PubMed  Google Scholar 

  13. Gallus, S. et al. Dietary zinc and prostate cancer risk: a case-control study from Italy. Eur. Urol. 52, 1052–1056 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Key, T. J., Silcocks, P. B., Davey, G. K., Appleby, P. N. & Bishop, D. T. A case-control study of diet and prostate cancer. Br. J. Cancer 76, 678–687 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kristal, A. R., Stanford, J. L., Cohen, J. H., Wicklund, K. & Patterson, R. E. Vitamin and mineral supplement use is associated with reduced risk of prostate cancer. Cancer Epidemiol. Biomarkers Prev. 8, 887–892 (1999).

    CAS  PubMed  Google Scholar 

  16. Lee, M. M. et al. Case-control study of diet and prostate cancer in China. Cancer Causes Control 9, 545–552 (1998).

    Article  CAS  PubMed  Google Scholar 

  17. Leitzmann, M. F. et al. Zinc supplement use and risk of prostate cancer. J. Natl Cancer Inst. 95, 1004–1007 (2003).

    Article  CAS  PubMed  Google Scholar 

  18. Zhang, Y., Coogan, P., Palmer, J. R., Strom, B. L. & Rosenberg, L. Vitamin and mineral use and risk of prostate cancer: the case-control surveillance study. Cancer Causes Control 20, 691–698 (2009).

    Article  CAS  PubMed  Google Scholar 

  19. Zaichick, V. Ye., Sviridova, T. V. & Zaichick, S. V. Zinc in the human prostate gland: normal, hyperplastic and cancerous. Int. Urol. Nephrol. 29, 565–574 (1997).

    Article  PubMed  Google Scholar 

  20. Ogunlewe, J. O. & Osegbe, D. N. Zinc and cadmium concentrations in indigenous blacks with normal, hypertrophic, and malignant prostate. Cancer 63, 1388–1392 (1989).

    Article  CAS  PubMed  Google Scholar 

  21. Costello, L. C. & Franklin, R. B. Zinc is decreased in prostate cancer: an established relationship of prostate cancer! J. Biol. Inorg. Chem. 16, 3–8 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Christudoss, P., Selvakumar, R., Fleming, J. J. & Gopalakrishnan, G. Zinc status of patients with benign prostatic hyperplasia and prostate carcinoma. Indian J. Urol. 27, 14–18 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  23. Costello, L. C. & Franklin, R. B. Novel role of zinc in the regulation of prostate citrate metabolism and its implications in prostate cancer. Prostate 35, 285–296 (1998).

    Article  CAS  PubMed  Google Scholar 

  24. Huang, L., Kirschke, C. P. & Zhang, Y. Decreased intracellular zinc in human tumorigenic prostate epithelial cells: a possible role in prostate cancer progression. Cancer Cell. Int. 6, 10 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Singh, K. K., Desouki, M. M., Franklin, R. B. & Costello, L. C. Mitochondrial aconitase and citrate metabolism in malignant and nonmalignant human prostate tissues. Mol. Cancer 5, 14 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Costello, L. C. & Franklin, R. B. The intermediary metabolism of the prostate: a key to understanding the pathogenesis and progression of prostate malignancy. Oncology 59, 269–282 (2000).

    Article  CAS  PubMed  Google Scholar 

  27. Liang, J. Y. et al. Inhibitory effect of zinc on human prostatic carcinoma cell growth. Prostate 40, 200–207 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Han, C. T., Schoene, N. W. & Lei, K. Y. Influence of zinc deficiency on Akt-Mdm2-p53 and Akt-p21 signaling axes in normal and malignant human prostate cells. Am. J. Physiol. Cell Physiol. 297, C1188–C1199 (2009).

    Article  CAS  PubMed  Google Scholar 

  29. Uzzo, R. G. et al. Diverse effects of zinc on NF-kappaB and AP-1 transcription factors: implications for prostate cancer progression. Carcinogenesis 27, 1980–1990 (2006).

    Article  CAS  PubMed  Google Scholar 

  30. Nardinocchi, L. et al. Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo. PLoS One 5, e15048 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Feng, P., Li, T. L., Guan, Z. X., Franklin, R. B. & Costello, L. C. Direct effect of zinc on mitochondrial apoptogenesis in prostate cells. Prostate 52, 311–318 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Feng, P. et al. Zinc induces mitochondria apoptogenesis in prostate cells. Mol. Urol. 4, 31–36 (2000).

    CAS  PubMed  Google Scholar 

  33. Feng, P., Li, T., Guan, Z., Franklin, R. B. & Costello, L. C. The involvement of Bax in zinc-induced mitochondrial apoptogenesis in malignant prostate cells. Mol. Cancer 7, 25 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Ku, J. H., Seo, S. Y., Kwak, C. & Kim, H. H. The role of survivin and Bcl-2 in zinc-induced apoptosis in prostate cancer cells. Urol. Oncol. 30, 562–568 (2012).

    Article  CAS  PubMed  Google Scholar 

  35. Ishii, K. et al. Evidence that the prostate-specific antigen (PSA)/Zn2+ axis may play a role in human prostate cancer cell invasion. Cancer Lett. 207, 79–87 (2004).

    Article  CAS  PubMed  Google Scholar 

  36. Ishii, K. et al. Aminopeptidase N regulated by zinc in human prostate participates in tumor cell invasion. Int. J. Cancer 92, 49–54 (2001).

    Article  CAS  PubMed  Google Scholar 

  37. Wickstrom, M., Larsson, R., Nygren, P. & Gullbo, J. Aminopeptidase N (CD13) as a target for cancer chemotherapy. Cancer Sci. 102, 501–508 (2011).

    Article  CAS  PubMed  Google Scholar 

  38. Goel, T. & Sankhwar, S. N. Comparative study of zinc levels in benign and malignant lesions of the prostate. Scand. J. Urol. Nephrol. 40, 108–112 (2006).

    Article  CAS  PubMed  Google Scholar 

  39. McMahon, R. J. & Cousins, R. J. Regulation of the zinc transporter ZnT-1 by dietary zinc. Proc. Natl Acad. Sci. USA 95, 4841–4846 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Cousins, R. J., Liuzzi, J. P. & Lichten, L. A. Mammalian zinc transport, trafficking, and signals. J. Biol. Chem. 281, 24085–24089 (2006).

    Article  CAS  PubMed  Google Scholar 

  41. Kambe, T., Yamaguchi-Iwai, Y., Sasaki, R. & Nagao, M. Overview of mammalian zinc transporters. Cell. Mol. Life Sci. 61, 49–68 (2004).

    Article  CAS  PubMed  Google Scholar 

  42. Liuzzi, J. P. & Cousins, R. J. Mammalian zinc transporters. Annu. Rev. Nutr. 24, 151–172 (2004).

    Article  CAS  PubMed  Google Scholar 

  43. Foster, M., Hancock, D., Petocz, P. & Samman, S. Zinc transporter genes are coordinately expressed in men and women independently of dietary or plasma zinc. J. Nutr. 141, 1195–1201 (2011).

    Article  CAS  PubMed  Google Scholar 

  44. Hasumi, M. et al. Regulation of metallothionein and zinc transporter expression in human prostate cancer cells and tissues. Cancer Lett. 200, 187–195 (2003).

    Article  CAS  PubMed  Google Scholar 

  45. Majumder, S. et al. Chromium(VI) down-regulates heavy metal-induced metallothionein gene transcription by modifying transactivation potential of the key transcription factor, metal-responsive transcription factor 1. J. Biol. Chem. 278, 26216–26226 (2003).

    Article  CAS  PubMed  Google Scholar 

  46. Iguchi, K. et al. Zinc and metallothionein levels and expression of zinc transporters in androgen-independent subline of LNCaP cells. J. Androl. 25, 154–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  47. Tepaamorndech, S., Huang, L. & Kirschke, C. P. A null-mutation in the Znt7 gene accelerates prostate tumor formation in a transgenic adenocarcinoma mouse prostate model. Cancer Lett. 308, 33–42 (2011).

    Article  CAS  PubMed  Google Scholar 

  48. Gaither, L. A. & Eide, D. J. The human ZIP1 transporter mediates zinc uptake in human K562 erythroleukemia cells. J. Biol. Chem. 276, 22258–22264 (2001).

    Article  CAS  PubMed  Google Scholar 

  49. Gaither, L. A. & Eide, D. J. Functional expression of the human hZIP2 zinc transporter. J. Biol. Chem. 275, 5560–5564 (2000).

    Article  CAS  PubMed  Google Scholar 

  50. Costello, L. C., Liu, Y., Zou, J. & Franklin, R. B. Evidence for a zinc uptake transporter in human prostate cancer cells which is regulated by prolactin and testosterone. J. Biol. Chem. 274, 17499–17504 (1999).

    Article  CAS  PubMed  Google Scholar 

  51. Eide, D. J. The SLC39 family of metal ion transporters. Pflugers Arch. 447, 796–800 (2004).

    Article  CAS  PubMed  Google Scholar 

  52. Dufner-Beattie, J., Huang, Z. L., Geiser, J., Xu, W. & Andrews, G. K. Mouse ZIP1 and ZIP3 genes together are essential for adaptation to dietary zinc deficiency during pregnancy. Genesis 44, 239–251 (2006).

    Article  CAS  PubMed  Google Scholar 

  53. Kim, B. E. et al. Zn2+-stimulated endocytosis of the mZIP4 zinc transporter regulates its location at the plasma membrane. J. Biol. Chem. 279, 4523–4530 (2004).

    Article  CAS  PubMed  Google Scholar 

  54. Desouki, M. M., Geradts, J., Milon, B., Franklin, R. B. & Costello, L. C. hZip2 and hZip3 zinc transporters are down regulated in human prostate adenocarcinomatous glands. Mol. Cancer 6, 37 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Chen, Q. G. et al. The role of zinc transporter ZIP4 in prostate carcinoma. Urol. Oncol. 30, 906–911 (2012).

    Article  CAS  PubMed  Google Scholar 

  56. Rishi, I. et al. Prostate cancer in African American men is associated with downregulation of zinc transporters. Appl. Immunohistochem. Mol. Morphol. 11, 253–260 (2003).

    Article  CAS  PubMed  Google Scholar 

  57. Franklin, R. B. et al. hZIP1 zinc uptake transporter down regulation and zinc depletion in prostate cancer. Mol. Cancer 4, 32 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Franklin, R. B. et al. Human ZIP1 is a major zinc uptake transporter for the accumulation of zinc in prostate cells. J. Inorg. Biochem. 96, 435–442 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Makhov, P. B. et al. Reversal of epigenetic silencing of AP-2α results in increased zinc uptake in DU-145 and LNCaP prostate cancer cells. Carcinogenesis 32, 1773–1781 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Mihelich, B. L. et al. miR-183-96-182 cluster is overexpressed in prostate tissue and regulates zinc homeostasis in prostate cells. J. Biol. Chem. 286, 44503–44511 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Milon, B. C., Agyapong, A., Bautista, R., Costello, L. C. & Franklin, R. B. Ras responsive element binding protein-1 (RREB-1) down-regulates hZIP1 expression in prostate cancer cells. Prostate 70, 288–296 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Zou, J., Milon, B. C., Desouki, M. M., Costello, L. C. & Franklin, R. B. hZIP1 zinc transporter down-regulation in prostate cancer involves the overexpression of ras responsive element binding protein-1 (RREB-1). Prostate doi:10.1002/pros.21368.

  63. Costello, L. C. & Franklin, R. B. Re: Silvano Gallus, Roberto Foschi, Eva Negri et al. Dietary zinc and prostate cancer risk: a case-control study from Italy. Eur. Urol. 2007;52:1052–7. Eur. Urol. 52, 1262–1263 (2007).

    Article  PubMed  Google Scholar 

  64. Costello, L. C., Franklin, R. B., Feng, P. & Tan, M. Re: zinc supplement use and risk of prostate cancer. J. Natl Cancer Inst. 96, 239–240 (2004).

    Article  CAS  PubMed  Google Scholar 

  65. Costello, L. C., Franklin, R. B., Feng, P., Tan, M. & Bagasra, O. Zinc and prostate cancer: a critical scientific, medical, and public interest issue (United States). Cancer Causes Control 16, 901–915 (2005).

    Article  PubMed  Google Scholar 

  66. Franklin, R. B. & Costello, L. C. Re: Vitamin and mineral use and risk of prostate cancer: the case-control surveillance: Zhang et al. Cancer Causes Control 20, 1529–1531 (2009).

    Article  PubMed  Google Scholar 

  67. Prasad, A. S. et al. Dietary zinc and prostate cancer in the TRAMP mouse model. J. Med. Food 13, 70–76 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Banudevi, S. et al. Chemopreventive effects of zinc on prostate carcinogenesis induced by N-methyl-N-nitrosourea and testosterone in adult male Sprague-Dawley rats. J. Cancer Res. Clin. Oncol. 137, 677–686 (2011).

    Article  CAS  PubMed  Google Scholar 

  69. Banudevi, S. et al. Protective effect of zinc on N-methyl-N-nitrosourea and testosterone-induced prostatic intraepithelial neoplasia in the dorsolateral prostate of Sprague Dawley rats. Exp. Biol. Med. (Maywood) 236, 1012–1021 (2011).

    Article  CAS  Google Scholar 

  70. Platz, E. A. et al. Prediagnostic toenail cadmium and zinc and subsequent prostate cancer risk. Prostate 52, 288–296 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Epstein, M. M. et al. Dietary zinc and prostate cancer survival in a Swedish cohort. Am. J. Clin. Nutr. 93, 586–593 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gonzalez, A., Peters, U., Lampe, J. W. & White, E. Zinc intake from supplements and diet and prostate cancer. Nutr. Cancer 61, 206–215 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Mayo Clinic. Zinc [online], (2012).

  74. Chandra, R. K. Excessive intake of zinc impairs immune responses. JAMA 252, 1443–1446 (1984).

    Article  CAS  PubMed  Google Scholar 

  75. Samman, S. & Roberts, D. C. The effect of zinc supplements on lipoproteins and copper status. Atherosclerosis 70, 247–252 (1988).

    Article  CAS  PubMed  Google Scholar 

  76. King, J. C., Shames, D. M. & Woodhouse, L. R. Zinc homeostasis in humans. J. Nutr. 130 (5S Suppl.), 1360S–1366S (2000).

    Article  CAS  PubMed  Google Scholar 

  77. Park, S. Y., Wilkens, L. R., Morris, J. S., Henderson, B. E. & Kolonel, L. N. Serum zinc and prostate cancer risk in a nested case-control study: the multiethnic cohort. Prostate 73, 261–266 (2013).

    Article  CAS  PubMed  Google Scholar 

  78. Lawson, K. A. et al. Multivitamin use and risk of prostate cancer in the National Institutes of Health-AARP Diet and Health Study. J. Natl Cancer Inst. 99, 754–764 (2007).

    Article  CAS  PubMed  Google Scholar 

  79. Uzzo, R. G. et al. Prevalence and patterns of self-initiated nutritional supplementation in men at high risk of prostate cancer. BJU Int. 93, 955–960 (2004).

    Article  CAS  PubMed  Google Scholar 

  80. Krone, C. A. & Harms, L. C. Re: Zinc supplement use and risk of prostate cancer. J. Natl Cancer Inst. 95, 1556–1557 (2003).

    Article  PubMed  Google Scholar 

  81. Krone, C. A., Wyse, E. J. & Ely, J. T. Cadmium in zinc-containing mineral supplements. Int. J. Food Sci. Nutr. 52, 379–382 (2001).

    Article  CAS  PubMed  Google Scholar 

  82. Achanzar, W. E. et al. Cadmium-induced malignant transformation of human prostate epithelial cells. Cancer Res. 61, 455–458 (2001).

    CAS  PubMed  Google Scholar 

  83. Johnson, L. A., Kanak, M. A., Kajdacsy-Balla, A., Pestaner, J. P. & Bagasra, O. Differential zinc accumulation and expression of human zinc transporter 1 (hZIP1) in prostate glands. Methods 52, 316–321 (2010).

    Article  CAS  PubMed  Google Scholar 

  84. Ghosh, S. K. et al. A novel imaging approach for early detection of prostate cancer based on endogenous zinc sensing. Cancer Res. 70, 6119–6127 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Cortesi, M. et al. Clinical assessment of the cancer diagnostic value of prostatic zinc: a comprehensive needle-biopsy study. Prostate 68, 994–1006 (2008).

    Article  CAS  PubMed  Google Scholar 

  86. Liguori, P. F. et al. Non-classical anticancer agents: synthesis and biological evaluation of zinc(II) heteroleptic complexes. Dalton Trans. 39, 4205–4212 (2010).

    Article  CAS  PubMed  Google Scholar 

  87. Ding, W. Q. & Lind, S. E. Metal ionophores—an emerging class of anticancer drugs. IUBMB Life 61, 1013–1018 (2009).

    Article  CAS  PubMed  Google Scholar 

  88. Costello, L. C. & Franklin, R. B. Cytotoxic/tumor suppressor role of zinc for the treatment of cancer: an enigma and an opportunity. Expert Rev. Anticancer Ther. 12, 121–128 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Killilea, A. N., Downing, K. H. & Killilea, D. W. Zinc deficiency reduces paclitaxel efficacy in LNCaP prostate cancer cells. Cancer Lett. 258, 70–79 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Magda, D. et al. Synthesis and anticancer properties of water-soluble zinc ionophores. Cancer Res. 68, 5318–5325 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  91. Shah, M. R. et al. Direct intra-tumoral injection of zinc-acetate halts tumor growth in a xenograft model of prostate cancer. J. Exp. Clin. Cancer Res. 28, 84 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  92. Makhov, P. et al. Docetaxel-mediated apoptosis in myeloid progenitor TF-1 cells is mitigated by zinc: potential implication for prostate cancer therapy. Prostate 71, 1413–1419 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Makhov, P. et al. Zinc chelation induces rapid depletion of the X-linked inhibitor of apoptosis and sensitizes prostate cancer cells to TRAIL-mediated apoptosis. Cell Death Differ. 15, 1745–1751 (2008).

    Article  CAS  PubMed  Google Scholar 

  94. Schimmer, A. D., Dalili, S., Batey, R. A. & Riedl, S. J. Targeting XIAP for the treatment of malignancy. Cell Death Differ. 13, 179–188 (2006).

    Article  CAS  PubMed  Google Scholar 

  95. Schimmer, A. D. et al. Small-molecule antagonists of apoptosis suppressor XIAP exhibit broad antitumor activity. Cancer Cell 5, 25–35 (2004).

    Article  CAS  PubMed  Google Scholar 

  96. Zuo, J. et al. Novel polypyridyl chelators deplete cellular zinc and destabilize the X-linked inhibitor of apoptosis protein (XIAP) prior to induction of apoptosis in human prostate and breast cancer cells. J. Cell. Biochem. 113, 2567–2575 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported in part by the National Institutes of Health Grants (RO1 CA134463, RO3 CA167671, CCSG, P30 CA006927) to V. Kolenko, the American Institute for Cancer Research Grant (09A023) to R. Uzzo and the Department of Defense Physician Research Training Award (W81XWH-10-1-0187) and Bucks County Board of Associates Award to A. Kutikov.

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  1. Department of Surgical Oncology, Fox Chase Cancer Center, 333 Cottman Avenue, Philadelphia, 19111-2497, PA, USA

    Vladimir Kolenko, Ervin Teper, Alexander Kutikov & Robert Uzzo

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V. Kolenko and A. Kutikov researched the data for the article. A. Kutikov and R. Uzzo discussed the article's content. V. Kolenko and E. Teper wrote the manuscript, after which V. Kolenko and R. Uzzo edited the manuscript before submission.

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Correspondence to Vladimir Kolenko.

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Kolenko, V., Teper, E., Kutikov, A. et al. Zinc and zinc transporters in prostate carcinogenesis. Nat Rev Urol 10, 219–226 (2013). https://doi.org/10.1038/nrurol.2013.43

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