The role of metallothionein in oncogenesis and cancer treatment
Anna Bizoń 1 , Kinga Jędryczko 1 , Halina Milnerowicz 1Abstract
Metallothionein is cysteine-rich low molecular mass protein. The involvement of MT in many physiological and pathophysiological processes such as apoptosis, proliferation, angiogenesis, and the detoxification of heavy metals suggested participation of this protein in carcinogenesis and tumor therapy.Depending on the type of tissue and classification of carcinoma various it was observed relation between MT expression and tumor type, stage, grade, poor prognosis and body resistance to radiotherapy and chemotherapy. MT in tumor cell plays important role in defense mechanism against the effect of radiation by inhibiting the processes that lead to the apoptosis. A number of studies have shown an increased expression of MT in various human tumors of larynx, pancreas, kidney, uterus and breast, whereas lower MT expression was detected in liver tumors. Variable MT expression was detected in case of thyroid, prostate, lung, stomach and central nervous system tumors.Also MT plays crucial role in the cytostatics treatment. MT can bind cis-platinum compounds and removes them from the cells, which may lead to multidrug resistance. However, the same functions of MT protect against the negative effects of chemotherapeutic treatment. It is especially important in case of heart cells.Analysis of MT expression in tumor cells may be useful in choosing method of treatment. It is difficult to determine whether increased expression of MT is only a inducing factor of the development of the carcinogenesis, its malignances and multidrug resistance, or it is a factor inhibiting the induction and development of cancer.
References
- 1. Abel J., de Ruiter N.: Inhibition of hydroxyl-radical-generated DNA degradation by metallothionein. Toxicol. Lett., 1989; 47: 191-196
Google Scholar - 2. Arriaga J.M., Bravo I.A., Bruno L., Morales-Bayo S., Hannois A., Sanchez-Loria F., Pairola F., Huertas E., Roberti M.P., Rocca Y.S., Aris M., Barrio M.M., Baffa-Trasci S., Levy E.M., Mordoh J., Bianchini M.: Combined metallothioneins and p53 proteins expression as a prognostic marker in patients with Dukes stage B and C colorectal cancer. Hum. Pathol., 2012; 43: 1695-1703
Google Scholar - 3. Athanassiadou P., Bantis A., Gonidi M., Athanassiades P., Agelonidou E., Grapsa D., Nikolopoulou P., Patsouris E.: The expression of metallothioneins on imprint smears of prostate carcinoma: correlation with clinicopathologic parameters and tumor proliferative capacity. Tumori, 2007; 93: 189-194
Google Scholar - 4. Bay B.H., Jin R., Huang J., Tan P.H.: Metallothionein as a prognostic biomarker in breast cancer. Exp. Biol. Med., 2006; 231: 1516-1521
Google Scholar - 5. Borges Junior P.C., Ribeiro R., Cardoso S.V., Berbet A., Rocha A., Espindola F.S., Loyola A.M.: Metallothionein immunolocalization in actinic skin nonmelanoma carcinomas. Appl. Immunohistochem. Mol. Morphol., 2007; 15: 165-169
Google Scholar - 6. Cai L., Cherian M.G., Iskander S., Leblanc M., Hammond R.R.: Metallothionein induction in human CNS in vitro: neuroprotection from ionizing radiation. Int. J. Radiat. Biol., 2000; 76: 1009-1017
Google Scholar - 7. Cardoso S.V., Barbosa H.M., Candellori I.M., Loyola A.M., Aguiar M.C.: Prognostic impact of metallothionein on oral squamous cell carcinoma. Virchows Arch., 2002; 441: 174-178
Google Scholar - 8. Carpenè E., Andreani G., Isani G.: Metallothionein functions and structural characteristics. J. Trace Elem. Med. Biol., 2007; 21, Suppl. 1: 35-39
Google Scholar - 9. Cherian M.G., Jayasurya A., Bay B.H.: Metallothioneins in human tumors and potential roles in carcinogenesis. Mutat. Res., 2003; 533: 201-209
Google Scholar - 10. Cherian M.G., Kang Y.J.: Metallothionein and liver cell regeneration. Exp. Biol. Med., 2006; 231: 138-144
Google Scholar - 11. Chimienti F., Seve M., Richard S., Mathieu J., Favier A.: Role of cellular zinc in programmed cell death: temporal relationship between zinc depletion, activation of caspases, and cleavage of Sp family transcription factors. Biochem. Pharmacol., 2001; 62: 51-62
Google Scholar - 12. Chung R.S., Penkowa M., Dittmann J., King C.E., Bartlett C., Asmussen J.W., Hidalgo J., Carrasco J., Leung Y.K., Walker A.K., Fung S.J., Dunlop S.A., Fitzgerald M., Beazley L.D., Chuah M.I., Vickers J.C., West A.K.: Redefining the role of metallothionein within the injured brain: extracellular metallothioneins play an important role in the astrocyte-neuron response to injury. J. Biol. Chem., 2008; 283: 15349-15358
Google Scholar - 13. Coyle P., Philcox J.C., Carey L.C. and Rofe A.M.: Metallothionein: The multipurpose protein. Cell. Mol. Life Sci., 2002; 59: 627-647
Google Scholar - 14. Dabrio M., Rodriguez A.R., Bordin G., Bebianno M.J., De Ley M., Sestakova I., Vasak M., Nordberg M.: Recent developments in quantification methods for metallothionein. J. Inorg. Biochem., 2002; 88: 123-134
Google Scholar - 15. Desoize B., Madoulet C.: Particular aspects of platinum compounds used at present in cancer treatment. Crit. Rev. Oncol. Hematol., 2002; 42: 317-325
Google Scholar - 16. Dutsch-Wicherek M., Sikora J., Tomaszewska R.: The possible biological role of metallothionein in apoptosis. Front. Biosci., 2008; 13: 4029-4038
Google Scholar - 17. Dzięgiel P.: Expression of metallothioneins in tumor cells. Pol. J. Pathol., 2004; 55: 3-12
Google Scholar - 18. Dziegiel P, Jeleń M, Muszczyńska B, Maciejczyk A, Szulc A, Podhorska-Okołów M, Cegielski M, Zabel M.: Role of metallothionein expression in non-small cell lung carcinomas. Rocz. Akad. Med. Bialymst., 2004; 49, Suppl. 1: 43-45
Google Scholar - 19. Ebert M.P., Günther T., Hoffmann J., Yu J., Miehlke S., Schulz H.U., Roessner A., Korc M., Malfertheiner P.: Expression of metallothionein II in intestinal metaplasia, dysplasia, and gastric cancer. Cancer Res., 2000; 60: 1995-2001
Google Scholar - 20. Ferrario C., Lavagni P., Gariboldi M., Miranda C., Losa M., Cleris L., Formelli F., Pilotti S., Pierotti M.A., Greco A.: Metallothionein 1G acts as an oncosupressor in papillary thyroid carcinoma. Lab. Invest., 2008; 88: 474-481
Google Scholar - 21. Gliński B., Mucha-Małecka A., Jakubowicz J., Frączek-Błachut B.: Rola radioterapii w leczeniu chorych z pierwotnymi i przerzutowymi guzami wątroby. Współ. Onkol., 2008; 12: 272-275
Google Scholar - 22. Gumulec J., Raudenska M., Adam V., Kizek R., Masarik M.: Metallothionein – immunohistochemical cancer biomarker: a meta-analysis. PLoS One, 2014; 9: e85346
Google Scholar - 23. Hishikawa Y., Koji T., Dhar D.K., Kinugasa S., Yamaguchi M., Nagasue N.: Metallothionein expression correlates with metastatic and proliferative potential in squamous cell carcinoma of the oesophagus. Br. J. Cancer, 1999; 81:712-720
Google Scholar - 24. Ioachim E., Assimakopoulos D., Peschos D., Zissi A., Skevas A., Agnantis N.J.: Immunohistochemical expression of metallothionein in benign premalignant and malignant epithelium of the larynx: correlation with p53 and proliferative cell nuclear antigen. Pathol. Res. Pract., 1999; 195: 809-814
Google Scholar - 25. Ioachim E., Assimakopoulos D., Peschos D., Zissi A., Skevas A., Agnantis N.J.: Immunohistochemical expression of metallothionein in benign premalignant and malignant epithelium of the larynx: correlation with p53 and proliferative cell nuclear antigen. Pathol. Res. Pract., 1999; 195: 809-814
Google Scholar - 26. Janssen A.M., van Duijn W., Kubben F.J., Griffioen G., Lamers C.B., van Krieken J.H., van de Velde C.J., Verspaget H.W.: Prognostic significance of metallothionein in human gastrointestinal cancer. Clin. Cancer Res., 2002; 8: 1889-1896
Google Scholar - 27. Janssen A.M., van Duijn W., Oostendorp-Van De Ruit M.M., Kruidenier L., Bosman C.B., Griffioen G., Lamers C.B., van Krieken J.H., van De Velde C.J., Verspaget H.W.: Metallothionein in human gastrointestinal cancer. J Pathol., 2000; 192: 293-300
Google Scholar - 28. Joseph M.G., Banerjee D., Kocha W., Feld R., Stitt L.W., Cherian M.G.: Metallothionein expression in patients with small cell carcinoma of the lung: correlation with other molecular markers and clinical outcome. Cancer, 2001; 92: 836-842
Google Scholar - 29. Kang Y.J., Zhou Z.X., Wang G.W., Buridi A., Klein J.B.: Suppression by metallothionein of doxorubicin-induced cardiomyocyte apoptosis through inhibition of p38 mitogen-activated protein kinases. J. Biol. Chem., 2000; 275:13690-13698
Google Scholar - 30. Karotki A.V., Vasák M.: Reaction of human metallothionein-3 with cisplatin and transplatin. J. Biol. Inorg. Chem., 2009; 14: 11291138
Google Scholar - 31. Kensova R., Kremplova R., Smerkova K., Zitka O., Hynek D., Adam V., Beklova M., Trnkova L., Stibrova M., Eckschlager T., Hubalek J., Kizek R.: Interactions of platinium-based cytostatics with metallothinein revealed by electrochemistry. Int. J. Electrochem. Sci., 2013; 8: 4472-4484
Google Scholar - 32. Kondo Y., Woo E.S., Michalska A.E., Choo K.H., Lazo J.S.: Metallothionein null cells have increased sensitivity to anticancer drugs. Canc. Res., 1995; 55: 2021-2023
Google Scholar - 33. Krizkova S., Fabrik I., Adam V., Hrabeta J., Eckschlager T., Kizek R.: Metallothionein – a promising tool for cancer diagnostics. Bratisl. Lek. List., 2009; 110: 93-97
Google Scholar - 34. 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
Google Scholar - 35. Królicka A., Kobierzycki C., Puła B., Podhorska-Okołów M., Piotrowska A., Rzeszutko M., Rzeszutko W., Rabczyński J., Domosławski P., Wojtczak B., Dawiskiba J., Dzięgiel P.: Comparison of metallothionein (MT) and Ki-67 antigen expression in benign and malignant thyroid tumours. Anticancer Res., 2010; 30: 4945-4949
Google Scholar - 36. Kundu J.K., Surh Y.J.: Inflammation: gearing the journey to cancer. Mutat. Res., 2008; 659: 15-30
Google Scholar - 37. Lansdown A.B.: Metallothioneins: potential therapeutic aids for wound healing in the skin. Wound Repair Regen., 2002; 10: 130-132
Google Scholar - 38. Lynes M.A., Zaffuto K., Unfricht D.W., Marusov G., Samson J.S., Yin X.: The physiological roles of extracellular metallothionein. Exp. Biol. Med., 2006; 231: 1548-1554
Google Scholar - 39. Madej J.A., Madej P., Kamiński K., Milnerowicz H., Łagan J., Nowak M., Dzimira S.: Immunohistochemiczna lokalizacja metalotioneiny (MT) w mięśniakach macicy u kobiet. Klin. Perinat. Ginekol., 2003; 39: 31-34
Google Scholar - 40. Madej J.A., Milnerowicz H., Dzimira S.: Immunohistochemiczna lokalizacja metalotioneiny (MT) w nowotworach nabłonkowych u zwierząt. Medycyna Wet., 1999; 55: 806-808
Google Scholar - 41. Madej J.A., Milnerowicz H., Dzimira S., Nowak M.: Immunocytochemiczna lokalizacja metalotioneiny w chłoniakach złośliwych u psów. Medycyna Wet., 2002; 58: 857-859
Google Scholar - 42. Madej J.A., Milnerowicz H., Kuryszko J., Dzimira S., Kapuśniak V.: Immunohistochemical localisation of metallotionein in leukemic lymphocytes in BLV – infected cattle. Pol. J. Vet. Sci,, 2000; 3: 227-230
Google Scholar - 43. Manso Y., Adlard P.A., Carrasco J., Vašák M., Hidalgo J.: Metallothionein and brain inflammation. J. Biol. Inorg. Chem., 2011; 16: 1103-1113
Google Scholar - 44. Margoshes M., Vallee B.L.: A cadmium protein from equine kidney cortex. J. Am. Chem. Soc., 1957; 79: 4813-4814
Google Scholar - 45. McCluggage W.G., Maxwell P., Bharucha H.: Immunohistochemical detection of metallothionein and MIB1 in uterine cervical squamous lesions. Int. J. Gynecol. Pathol., 1998; 17: 29-35
Google Scholar - 46. Milnerowicz H, Bizoń A.: Determination of metallothionein in biological fluids using enzyme-linked immunoassay with commercial antibody. Acta Biochim. Pol., 2010; 57: 99-104
Google Scholar - 47. Milnerowicz H., Jabłonowska M., Bizoń A.: Change of zinc, copper, and metallothionein concentrations and the copper-zinc superoxide dismutase activity in patients with pancreatitis. Pancreas, 2009; 38: 681-688
Google Scholar - 48. Mitropoulos D., Kyroudi-Voulgari A., Theocharis S., Serafetinides E., Moraitis E., Zervas A., Kittas C.: Prognostic significance of metallothionein expression in renal cell carcinoma. World J. Surg. Oncol., 2005; 3: 5
Google Scholar - 49. Miura T., Muraoka S., Ogiso T.: Antioxidant activity of metallothionein compared with reduced glutathione. Life Sci., 1997; 60: 301-309
Google Scholar - 50. Miyashita H., Sato Y.: Metallothionein 1 is a downstream target of vascular endothelial zinc finger 1 (VEZF1) in endothelial cells and participates in the regulation of angiogenesis. Endothelium, 2005; 12: 163-170
Google Scholar - 51. Nielsen A.E., Bohr A., Penkowa M.: The balance between life and death of cells: roles of metallothioneins. Biomark. Insights, 2006; 1: 99-111
Google Scholar - 52. Nowak M., Madej J.A., Dzięgiel P.: Expresja metalotioneiny i jej korelacja z antygenem Ki-67 w gruczolakorakach gruczołu sutkowego suk. Medycyna Wet., 2006; 62: 427-431
Google Scholar - 53. Nowak M., Madej J.A., Dzięgiel P.: Extent of metallotionein expression in correlation with expression of Ki-67 antigen in soft tissue fibrosacromas in dogs. Bull. Vet. Inst. Pulawy, 2007; 51: 139-144
Google Scholar - 54. Ohshio G., Imamura T., Okada N., Wang Z.H., Yamaki K., Kyogoku T., Suwa H., Yamabe H., Imamura M.: Immunohistochemical study of metallothionein in pancreatic carcinomas. J. Cancer Res. Clin. Oncol., 1996; 122: 351-355
Google Scholar - 55. Pastuszewski W., Dzięgiel P., Kręcicki T., Podhorska-Okołów M., Ciesielska U., Gorzyńska E., Zabel M.: Prognostic significance of metallothionein, p53 protein and Ki-67 antigen expression in laryngeal cancer. Anticancer Res., 2007; 27: 335-342
Google Scholar - 56. Pedersen M.Ø., Larsen A., Stoltenberg M., Penkowa M.: The role of metallothionein in oncogenesis and cancer prognosis. Prog. Histochem. Cytochem., 2009; 44: 29-64
Google Scholar - 57. Przybyszewski W.M., Wideł M., Rzeszowska-Wolny J.: Kardiotoksyczne następstwa promieniowania jonizującego i antracyklin. Postępy Hig. Med. Dośw., 2006; 60: 397-405
Google Scholar - 58. 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
Google Scholar - 59. Sabolić I., Breljak D., Skarica M., Herak-Kramberger C.M.: Role of metallothionein in cadmium traffic an toxicity in kidneys and other mammalian organs. Biometals, 2010; 23: 897-926
Google Scholar - 60. Schiller J.T., Lowy D.R.: Virus infection and human cancer: an overview. Recent Results Cancer Res., 2014; 193: 1-10
Google Scholar - 61. Shibuya K., Nishimura N., Suzuki J.S., Tohyama C., Naganuma A., Satoh M.: Role of metallothionein as a protective factor against radiation carcinogenesis. J. Toxicol. Sci., 2008; 33: 651-655
Google Scholar - 62. Shibuya K., Suzuki J.S., Kito H., Naganuma A., Tohyama C., Satoh M.: Protective role of metallothionein in bone marrow injury caused by X-irradiation. J. Toxicol. Sci., 2008; 33: 479-484
Google Scholar - 63. Stępkowska I.M.: Właściwości biologiczne metalotionein i ich udział w procesach oksydoredukcyjnych w komórkach, ze szczególnym uwzględnieniem ośrodkowego układu nerwowego człowieka. Postępy Biol. Komórki, 2010; 37: 869-885
Google Scholar - 64. Surowiak P., Materna V., Gyorffy B., Matkowski R., Wojnar A., Maciejczyk A., Paluchowski P., Dzięgiel P., Pudełko M., Kornafel J., Dietel M., Kristiansen G., Zabel M., Lage H.: Multivariate analysis of oestrogen receptor alpha, pS2, metallothionein and CD24 expression in invasive breast cancers. Br. J. Cancer, 2006; 95: 339-346
Google Scholar - 65. Suzuki J.S., Nishimura N., Zhang B., Nakatsuru Y., Kobayashi S., Satoh M., Tohyama C.: Metallothionein deficiency enhances skin carcinogenesis induced by 7,12-dimethylbenz[α]anthracene and 12-O-tetradecanoylphorbol-13-acetate in metallothionein-null mice. Carcinogenesis, 2003; 24: 1123-1132
Google Scholar - 66. Szuławska A., Czyż M.: Molekularne mechanizmy działania antracyklin. Postępy Hig. Med. Dośw., 2006; 60: 78-100
Google Scholar - 67. Ścibior-Bentkowska D., Czeczot H.: Komórki nowotworowe a stres oksydacyjny. Postępy Hig. Med. Dośw., 2009; 63: 58-72
Google Scholar - 68. Śliwińska-Mossoń M., Milnerowicz H., Rabczyński J., Milnerowicz S.: Immunohistochemical localization of metallothionein and p53 protein in pancreatic serous cystadenomas. Arch. Immunol. Ther. Exp., 2009; 57: 295-301
Google Scholar - 69. Ślosarek K.: Podstawy planowania leczenia w radioterapii na podstawie skryptu kursu „Praktyczne aspekty współczesnej radioterapii”, Polskie Towarzystwo Onkologiczne Oddział Śląski, Gliwice 2007, 95-134
Google Scholar - 70. Tao X., Zheng J.M., Xu A.M., Chen X.F., Zhang S.H.: Downregulated expression of metallothionein and its clinicopathological significance in hepatocellular carcinoma. Hepatol. Res., 2007; 37: 820-827
Google Scholar - 71. Theocharis S.E., Margeli A.P., Koutselinis A.: Metallothionein: a multifunctional protein from toxicity to cancer. Int. J. Biol. Markers, 2003;18:162-169
Google Scholar - 72. Thirumoorthy N., Manisenthil Kumar K.T., Shyam Sundar A., Panayappan L., Chatterjee M.: Metallothionein: an overview. World J. Gastroenteral., 2007; 13: 993-996
Google Scholar - 73. Trynda-Lemiesz L., Śliwińska-Hill U.: Kompleksy metali w terapii nowotworowej. Teraźniejszość i przyszłość, Nowotwory J. Oncol., 2011; 61:, 465-474
Google Scholar - 74. Tuccari G., Giuffrè G., Arena F., Barresi G.: Immunohistochemical detection of metallothionein in carcinomatous and normal human gastric mucosa. Histol. Histopathol., 2000; 15: 1035-1041
Google Scholar - 75. Tüzel E., Kirkali Z., Yörükoglu K., Mungan M.U., Sade M.: Metallothionein expression in renal cell carcinoma: subcellular localization and prognostic significance. J. Urol., 2001; 165: 1710-1713
Google Scholar - 76. Valko M., Rhodes C.J., Moncol J., Izakovic M., Mazur M.: Free radicals, metals and antioxidants in oxidative stress-induced cancer. Chem. Biol. Intract., 2006; 160: 1-40
Google Scholar - 77. Vasak M.: Advances in metallothionein structure and functions. J. Trace Elem. Med. Biol., 2005; 19: 13-17
Google Scholar - 78. Wang N., Dong C.R., Jiang R., Tang C., Yang L., Jiang Q.F., Chen G.G., Liu Z.M.: Overexpression of HIF-1α, metallothionein and SLUG is associated with high TNM stage and lymph node metastasis in papillary thyroid carcinoma. Int. J. Clin. Exp. Pathol., 2014; 7: 322-330
Google Scholar - 79. 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: 7
Google Scholar - 80. Weinlich G., Topar G., Eisendle K., Fritsch P.O., Zelger B.: Comparison of metallothionein-overexpression with sentinel lymph node biopsy as prognostic factors in melanoma. J. Eur. Acad. Dermatol. Venereol., 2007; 21: 669-677
Google Scholar - 81. Werynska B., Pula B., Muszczynska-Bernhard B., Gomulkiewicz A., Piotrowska A., Prus R., Podhorska-Okolow M., Jankowska R., Dziegiel P.: Metallothionein 1F and 2A overexpression predicts poor outcome of non-small cell lung cancer patients. Exp. Mol. Pathol., 2013; 94: 301-308
Google Scholar - 82. Wronkowski Z., Brużewicz S.: Chemioterapia i radioterapia. PZWL Warszawa 2007; 45-124
Google Scholar - 83. Yamasaki M., Nomura T., Sato F., Mimata H.: Metallothionein is up-regulated under hypoxia and promotes the survival of human prostate cancer cells. Oncol. Rep., 2007; 18: 1145-1153
Google Scholar