Zinc and metallothionen in prostate cancer: A review

Zinc is an essential and the second most abundant trace element in humans. Zinc is a structural component of different proteins involved in the transcriptional machinery, such as transcription factors and ribosomes and the presence of zinc is also necessary for DNA synthesis. Zinc not only improves cell mediated immune functions but also functions as an antioxidant and anti-inflammatory agent. Oxidative stress and chronic inflammation have been implicated in development of many cancers. Various types of tumor cell lines have been used to investigate the cellular effects of zinc ions and its connection with metallothioneins (MTs). Dietary zinc deficiency is associated with oxidative stress in the reproductive organs with consequent decline in MTs levels indicative of association of MTs expression and apoptosis and perturbation of homeostatic zinc level. Treatment of prostate cancer with zinc causes an increase in MTs expression, which is significantly associated with resistance to cisplatin chemotherapy and radiotherapy in prostate cancer. We review the role and recent advances of zinc and MTs in prostate cancer in the last years.

1. McCarthy, T.J.; Zeelie, J.J.; Krause, D.J. THE ANTIMICROBIAL ACTION OF ZINC ION ANTIOXIDANT COMBINATIONS. Journal of Clinical Pharmacy and Therapeutics 1992, 17, 51-54.
2. Solomons, N.W. Mild human zinc deficiency produces an imbalance between cell-mediated and humoral immunity. Nutrition Reviews 1998, 56, 27-28.
3. Ho, E. Zinc deficiency, DNA damage and cancer risk. Journal of Nutritional Biochemistry 2004, 15, 572-578.
4. Alam, S.; Kelleher, S.L. Cellular Mechanisms of Zinc Dysregulation: A Perspective on Zinc Homeostasis as an Etiological Factor in the Development and Progression of Breast Cancer. Nutrients 2012, 4, 875-903.
5. Krizkova, S.; Ryvolova, M.; Hrabeta, J.; Adam, V.; Stiborova, M.; Eckschlager, T.; Kizek, R. Metallothioneins and zinc in cancer diagnosis and therapy. Drug Metab. Rev. 2012, 44, 287-301.
6. Ruttkay-Nedecky, B.; Nejdl, L.; Gumulec, J.; Zitka, O.; Masarik, M.; Eckschlager, T.; Stiborova, M.; Adam, V.; Kizek, R. The Role of Metallothionein in Oxidative Stress. Int. J. Mol. Sci. 2013, 14, 6044- 6066.
7. Mehus, A.A.; Muhonen, W.W.; Garrett, S.H.; Somji, S.; Sens, D.A.; Shabb, J.B. Quantitation of Human Metallothionein Isoforms: A Family of Small, Highly Conserved, Cysteine-rich Proteins*. Molecular & Cellular Proteomics 2014, 13, 1020- 1033.
8. Mididoddi, S.; McGuirt, J.P.; Sens, M.A.; Todd, J.H.; Sens, D.A. Isoform-specific expression of metallothionein mRNA in the developing and adult human kidney. Toxicology Letters 1996, 85, 17-27.
9. Werynska, B.; Pula, B.; Kobierzycki, C.; Dziegiel, P.; Podhorska-Okolow, M. Metallothioneins in the lung cancer. Folia Histochem. Cytobiol. 2015, 53, 1-10.
10. Wei, H.; Desouki, M.M.; Lin, S.; Xiao, D.; Franklin, R.B.; Feng, P. Differential expression of metallothioneins (MTs) 1, 2, and 3 in response to zinc treatment in human prostate normal and malignant cells and tissues. Mol. Cancer 2008, 7.
11. Lin, S.-f.; Wei, H.; Maeder, D.; Franklin, R.B.; Feng, P. Profiling of zinc-altered gene expression in human prostate normal vs. cancer cells: a time course study. Journal of Nutritional Biochemistry 2009, 20, 1000-1012.
12. Horecka, A.; Pasternak, K. ZINC IN MEDICINE AND TREATMENT. Journal of Elementology 2014, 19, 607-616.
13. G r u m m t , F. ; W e i n m a n n d o r s c h , C . ; Schneiderschaulies, J.; Lux, A. Zinc as a 2nd messenger of mitogenic induction - effects on diadenosine tetraphosphate (ap4a) and DNAsynthesis. Experimental Cell Research 1986, 163, 191-200.
14. Prakash, A.; Bharti, K.; Majeed, A.A. Zinc: indications in brain disorders. Fundam. Clin. Pharmacol. 2015, 29, 131-149.
15. Truong-Tran, A.Q.; Carter, J.; Ruffin, R.; Zalewski, P.D. New insights into the role of zinc in the respiratory epithelium. Immunol. Cell Biol. 2001, 79, 170-177.
16. Haase, H.; Beyersmann, D. Intracellular zinc distribution and transport in C6 rat glioma cells. Biochemical and Biophysical Research Communications 2002, 296, 923-928.
17. Bonaventura, P.; Benedetti, G.; Albarede, F.; Miossec, P. Zinc and its role in immunity and inflammation. Autoimmun. Rev. 2015, 14, 277- 285.
18. Bao, B.; Prasad, A.S.; Beck, F.W.J.; Fitzgerald, J.T.; Snell, D.; Bao, G.W.; Singh, T.; Cardozo, L.J. Zinc decreases C-reactive protein, lipid peroxidation, and inflammatory cytokines in elderly subjects: a potential implication of zinc as an atheroprotective agent. American Journal of Clinical Nutrition 2010, 91, 1634-1641.
19. Hirano, T.; Murakami, M.; Fukada, T.; Nishida, K.; Yamasaki, S.; Suzuki, T. Roles of zinc and zinc signaling in immunity: Zinc as an intracellular signaling molecule. In Advances in Immunology, Vol 97; Alt, F. W.; Austen, K. F.; Honjo, T.; Melchers, F.; Uhr, J. W.; Unanue, E. R., Eds.; 2008; Vol. 97, pp. 149-176.
20. Prasad, A.S. Zinc: role in immunity, oxidative stress and chronic inflammation. Current Opinion in Clinical Nutrition and Metabolic Care 2009, 12, 646-652.
21. Rosenkranz, E.; Prasad, A.; Rink, L. Immunobiology and Hematology of Zinc. In Zinc in Human Health; Rink, L., Ed. 2011; Vol. 76, pp. 195-233.
22. Wong, C.P.; Ho, E. Zinc and its role in age-related inflammation and immune dysfunction. Mol. Nutr. Food Res. 2012, 56, 77-87.
23. John, E.; Laskow, T.C.; Buchser, W.J.; Pitt, B.R.; Basse, P.H.; Butterfield, L.H.; Kalinski, P.; Lotze, M.T. Zinc in innate and adaptive tumor immunity. J. Transl. Med. 2010, 8.
24. Evans, G.W. ZINC AND ITS DEFICIENCY DISEASES. Clinical Physiology and Biochemistry 1986, 4, 94-98.
25. Haase, H.; Rink, L. The immune system and the impact of zinc during aging. Immunity & ageing : I & A 2009, 6, 9.
26. Apostolova, M.D.; Ivanova, I.A.; Cherian, M.G. Signal transduction pathways, and nuclear translocation of zinc and metallothionein during differentiation of myoblasts. Biochemistry and Cell Biology-Biochimie Et Biologie Cellulaire 2000, 78, 27-37.
27. Karamyyar, M.; Gheibi, S.; Noroozi, M.; Kord Valeshabad, A. Therapeutic effects of oral zinc supplementation on acute watery diarrhea with moderate dehydration: a double-blind randomized clinical trial. Iranian journal of medical sciences 2013, 38, 93-99.
28. Overbeck, S.; Rink, L.; Haase, H. Modulating the immune response by oral zinc supplementation: a single approach for multiple diseases. Archivum Immunologiae Et Therapiae Experimentalis 2008, 56, 15-30. Journal of Metallomics and Nanotechnologies 2015, 2, 58—63 63
29. Prasad, A.S.; Beck, F.W.J.; Kaplan, J.; Chandrasekar, P.H.; Ortega, J.; Fitzgerald, J.T.; Swerdlow, P. Eff ect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD) (vol 61, pg 194, 1999). American Journal of Hematology 1999, 62, 127-127.
30. Bao, B.; Prasad, A.S.; Beck, F.W.J.; Snell, D.; Suneja, A.; Sarkar, F.H.; Doshi, N.; Fitzgerald, J.T.; Swerdlow, P. Zinc supplementation decreases oxidative stress, incidence of infection, and generation of infl ammatory cytokines in sickle cell disease patients. Translational Research 2008, 152, 67-80.
31. Ames, B.N. Micronutrient defi ciencies - A major cause of DNA damage. In Cancer Prevention: Novel Nutrient and Pharmaceutical Developments; Bradlow, H. L.; Fishman, J.; Osborne, M. P., Eds.; New York Acad Sciences: New York, 1999; Vol. 889, pp. 87-106.
32. Prasad, A.S.; Beck, F.W.J.; Snell, D.C.; Kucuk, O. Zinc in Cancer Prevention. Nutrition and Cancer-an International Journal 2009, 61, 879-887.
33. Taylor, K.M.; Morgan, H.E.; Smart, K.; Zahari, N.M.; Pumford, S.; Ellis, I.O.; Robertson, J.F.R.; Nicholson, R.I. Th e emerging role of the LIV-1 subfamily of zinc transporters in breast cancer. Mol. Med. 2007, 13, 396-406.
34. Costello, L.C.; Franklin, R.B. The intermediary metabolism of the prostate: A key to understanding the pathogenesis and progression of prostate malignancy. Oncology 2000, 59, 269-282.
35. 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 and Prostatic Diseases 2004, 7, 111-117.
36. Krizkova, S.; Ryvolova, M.; Gumulec, J.; Masarik, M.; Adam, V.; Majzlik, P.; Hubalek, J.; Provaznik, I.; Kizek, R. Electrophoretic fi ngerprint metallothionein analysis as a potential prostate cancer biomarker. Electrophoresis 2011, 32, 1952-1961.
37. Chun, J.H.; Kim, H.K.; Kim, E.; Kim, I.H.; Kim, J.H.; Chang, H.J.; Choi, I.J.; Lim, H.S.; Kim, I.J.; Kang, H.C.; Park, J.H.; Bae, J.M.; Park, J.G. Increased expression of metallothionein is associated with irinotecan resistance in gastric cancer. Cancer Res. 2004, 64, 4703-4706.
38. Yap, X.; Tan, H.-Y.; Huang, J.; Lai, Y.; Yip, G.W.-C.; Tan, P.-H.; Bay, B.-H. Over-expression of metallothionein predicts chemoresistance in breast cancer. Journal of Pathology 2009, 217, 563-570.
39. Ioachim, E.E.; Goussia, A.C.; Agnantis, N.J.; Machera, M.; Tsianos, E.V.; Kappas, A.M. Prognostic evaluation of metallothionein expression in human colorectal neoplasms. J. Clin. Pathol. 1999, 52, 876-879.
40. Saga, Y.; Hashimoto, H.; Yachiku, S.; Tokumitsu, M.; Kaneko, S. Immunohistochemical expression of metallothionein in human bladder cancer: Correlation with histopathological parameters and patient survival. Journal of Urology 2002, 168, 2227- 2231.
41. Han, Y.C.; Zheng, Z.L.; Zuo, Z.H.; Yu, Y.P.; Chen, R.; Tseng, G.C.; Nelson, J.B.; Luo, J.H. Metallothionein 1h tumour suppressor activity in prostate cancer is mediated by euchromatin methyltransferase 1. Journal of Pathology 2013, 230, 184-193.
42. Forma, E.; Krzeslak, A.; Wilkosz, J.; Jozwiak, P.; Szymczyk, A.; Rozanski, W.; Brys, M. Metallothionein 2A genetic polymorphisms and risk of prostate cancer in a Polish population. Cancer Genet. 2012, 205, 432-435.
43. Agrawal, R.; Bedwal, R.S. Effect of dietary zinc defi ciency on metallothionein concentration of epididymal luminal fl uids of weanling Wistar albino rats. Indian Journal of Experimental Biology 2003, 41, 118-122.
44. Joshi, S.; Nair, N.; Bedwal, R.S. Dietary Zinc Defi ciency Eff ects Dorso-lateral and Ventral Prostate of Wistar Rats: Histological, Biochemical and Trace Element Study. Biol. Trace Elem. Res. 2014, 161, 91-100.
45. Theocharis, S.E.; Margeli, A.P.; Koutselinis, A. Metallothionein: A multifunctional protein from toxicity to cancer. International Journal of Biological Markers 2003, 18, 162-169.
46. Th eocharis, S.E.; Margeli, A.P.; Klijanienko, J.T.; Kouraklis, G.P. Metallothionein expression in human neoplasia. Histopathology 2004, 45, 103-118.
47. Garrett, S.H.; Sens, M.A.; Shukla, D.; Flores, L.; Somji, S.; Todd, J.H.; Sens, D.A. Metallothionein isoform 1 and 2 gene expression in the human prostate: Downregulation of MT-1X in advanced prostate cancer. Prostate 2000, 43, 125-135.
48. Smith, D.J.; Jaggi, M.; Zhang, W.; Galich, A.; Du, C.; Sterrett, S.P.; Smith, L.M.; Balaji, K.C. Metallothioneins and resistance to cisplatin and radiation in prostate cancer. Urology 2006, 67, 1341- 1347.
49. Gumulec, J.; Masarik, M.; Krizkova, S.; Hlavna, M.; Babula, P.; Hrabec, R.; Rovny, A.; Masarikova, M.; Sochor, J.; Adam, V.; Eckschlager, T.; Kizek, R. Evaluation of alpha-methylacyl-CoA racemase, metallothionein and prostate specifi c antigen as prostate cancer prognostic markers. Neoplasma 2012, 59, 191-200.
50. Hlavna, M.; Raudenska, M.; Hudcova, K.; Gumulec, J.; Sztalmachova, M.; Tanhaeuserova, V.; Babula, P.; Adam, V.; Eckschlager, T.; Kizek, R.; Masarik, M. MicroRNAs and zinc metabolism-related gene expression in prostate cancer cell lines treated with zinc(II) ions. International Journal of Oncology 2012, 41, 2237-2244.
51. Albrecht, A.L.; Singh, R.K.; Somji, S.; Sens, M.A.; Sens, D.A.; Garrett, S.H. Basal and metal-induced expression of metallothionein isoform 1 and 2 genes in the RWPE-1 human prostate epithelial cell line. Journal of Applied Toxicology 2008, 28, 283-293

PDF