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Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma

  • Z. Burián
  • A. Ladányi
  • T. Barbai
  • V. Piurkó
  • T. Garay
  • E. Rásó
  • József TímárEmail author
Original Article
  • 60 Downloads

Abstract

Zinc as an essential trace metal is a ubiquitous component of various molecules of the cell. Studies indicated that it may modulate functions of various cancer cell types, and can even inhibit metastasis formation in experimental models. In melanoma, zinc was shown to affect melanin production and to induce apoptosis. Using human melanoma cell lines, we have tested the effects of ZnSO4 on cell proliferation, survival, migration as well as in vivo on experimental liver colony formation. We have found that ZnSO4 has antiproliferative and proapoptotic effects in vitro. In SCID mice intraperitoneal administration of ZnSO4 specifically inhibited liver colony formation without affecting primary tumor growth. To reveal the molecular mechanisms of action of zinc in human melanoma, we have tested mRNA expression of zinc finger transcription factors and found a strong inhibitory effect on HIF1α, as compared to WT1 whereas HIF2α and MTF1 expression was unaffected. Immunohistochemical detection of HIF1α protein in liver metastases confirmed its decreased nuclear expression after in vivo ZnSO4 treatment. These data indicate that in human melanoma zinc administration may have an antimetastatic effect due to a selective downregulation of HIF1α.

Keywords

ZnSO4 Human melanoma HIF1α Metastasis inhibition 

Notes

Acknowledgements

This work was supported by NKFIH-NAP-2017-1.2.1.-NKP-0002, KTIA-2017-SE, NKFIH-112371.

Compliance with Ethical Standards

Conflict of Interest

The authors of this manuscript declare no conflict of interest concerning of this manuscript.

References

  1. 1.
    Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Phys Rev 73:79–118Google Scholar
  2. 2.
    Grattan BJ, Freake HC (2012) Zinc and cancer: implications for LIV-1 in breast cancer. Nutrients 4:648–675CrossRefGoogle Scholar
  3. 3.
    Intsuka S, Araki S (1978) Plasma copper and zinc levels in patients with malignant tumors of digestive organs: clinical evaluation of the cu/Zn ratio. Cancer 42:626–631CrossRefGoogle Scholar
  4. 4.
    Hisaki T, Furumoto T, Nozaka K, Koga S (1988) Serum zinc and copper changes after gastrectomy in aged patients with gastric cancer. Jpn J Sur 18:158–163CrossRefGoogle Scholar
  5. 5.
    Prasad AS, Beck FW, Doerr TD, Shamsa FH, Mathog RH (1998) Nutritional and zinc status of head and neck cancer patients: an interpretive review. Am Coll Nutr 17:409–418CrossRefGoogle Scholar
  6. 6.
    Yucel I, Arpaci F, Ozet A, Berk O (1994) Serum copper and zinc levels and copper/zinc ratio in patients with breast cancer. Biol Trace Elem Res 40:31–38CrossRefGoogle Scholar
  7. 7.
    Igic PG, Lee E, Harper W, Roach KW (2012) Toxic effects associated with consumption of zinc. Mayo Clin Proc 77:713–716CrossRefGoogle Scholar
  8. 8.
    Fosmire GJ (1990) Zinc toxicity. Am J Clin Nutr 51:225–227CrossRefGoogle Scholar
  9. 9.
    Timar J, Raso R, Paku S, Kopper L (1998) Oral administration of a trace element preparation and zinc inhibit liver metastasis of 3LL-HH murine tumor cells. Int J Mol Med 2:105–113Google Scholar
  10. 10.
    Dubi N, Gheber L, Fisgman D, Sekler I, Hershfinkel M (2008) Extracellular zinc and zinc-citrate, acting through a putative zinc-sensing receptor, regulate growth and survival of prostate cancer cells. Carcinogenesis 29:1692–1702CrossRefGoogle Scholar
  11. 11.
    Hwang JJ, Kim HN, Kim J, Cho DH, Kim MJ, Kim YS, Kim Y, Park SJ, Koh JY (2010) Zinc(II) ion mediates tamoxifen-induced autophagy and cell death in MCF-7 breast cancer cell line. Biometals 23(6):997–1013CrossRefGoogle Scholar
  12. 12.
    Yamada H, Suzuki K, Koizumi S (2007) Gene expression profile in human cells exposed to zinc. J Toxicol Sci 32:193–196CrossRefGoogle Scholar
  13. 13.
    Kindermann B, Döring F, Pfaffl M, Daniel H (2004) Identification of genes responsive to intracellular zinc depletion in the human colon adenocarcinoma cell line HT-29. J Nutr 134:57–62CrossRefGoogle Scholar
  14. 14.
    Schadendorf D, vanAkkoi ACJ, Berking C, Griewank KG, Gutzmer R, Hauschild A et al (2018) Melanoma. Lancet 392:971–984CrossRefGoogle Scholar
  15. 15.
    Farmer PJ, Gidanian S, Shahandeh B, Di Bilio AJ, Tohidian N, Meyskens FL Jr. (2003) Melanin as a target for melanoma chemotherapy: pro-oxidant effect of oxygen and metals on melanoma viability. Pigment Cell Res 16:273–279Google Scholar
  16. 16.
    Ladányi A, Tímár J, Paku S, Molnár G, Lapis K (1990) Selection and characterization of human melanoma lines with different liver-colonizing capacity. Int J Cancer 46:456–461CrossRefGoogle Scholar
  17. 17.
    Timár J, Rásó E, Honn KV, Hagmann W (1999) 12-lipoxygenase expression in human melanoma cell lines. Adv Exp Med Biol 469:617–622CrossRefGoogle Scholar
  18. 18.
    Garay, T., E. Juhasz, E. Molnar, M. Eisenbauer, A. Czirok, B. Dekan,et al. (2013) Cell migration or cytokinesis and proliferation? - revisiting the "go or grow" hypothesis in cancer cells in vitro. Exp Cell Res 319:3094–3103Google Scholar
  19. 19.
    Wellinghausen N, Kirchner H, Rink L (1997) The immunobiology of zinc. Immunol Today 18:523–524CrossRefGoogle Scholar
  20. 20.
    Franklin RB, Costello LC (2009) The important role of the apoptotic effects of zinc in the development of cancers. J Cell Biochem 106:750–757CrossRefGoogle Scholar
  21. 21.
    Kim I, Kim CH, Seo GH, Kim HS, Lee J, Kim DG, Ahn YS (2008) Inhibitory effect of zinc on hypoxic HIF-1 activation in astrocytes. Neuroreport 19:1065–1068Google Scholar
  22. 22.
    Nardinocchi L, Pantisano V, Puca R, Porru M, Aiello A, Grasselli A, Leonetti C, Safran M, Rechavi G, Givol D, Farsetti A, D'Orazi G (2010) Zinc downregulates HIF-1α and inhibits its activity in tumor cells in vitro and in vivo. PLoS One 5:e15048CrossRefGoogle Scholar
  23. 23.
    Yuan Y, Hillind G, Ferguson T, Millhorn DE (2003) Cobalt inhibits the interaction between hypoxia inducible factor-a and von Hippel Lindau protein by direct binding to hypoxia inducible factor-a. J Biol Chem 278:15911–15916CrossRefGoogle Scholar
  24. 24.
    Chun YS, Choi E, Yeo EJ, Lee HJ, Kim MS, Park JW (2001) A new HIF1 alpha variant induced by zinc ion suppresses HIF1-mediated hypoxic responses. J Cell Sci 114:4051–4061Google Scholar
  25. 25.
    Nardinocchi L, Puca R, Sacchi A, Rechavi G, Givol D, D’Orazi G (2009) Targeting hypoxia in cancer cells by restoring homeodomain interacting protein-kinase 2 and p53 activity and suppressing HIF1-alpha. PlosOne 4:e6819CrossRefGoogle Scholar
  26. 26.
    Kuphal S, Winklmeier A, Warnecke C, Bosserhoff AK (2010) Constitutive HIF-1 activity in malignant melanoma. Eur J Cancer 46:1159–1169CrossRefGoogle Scholar
  27. 27.
    Zbytek B, Peacock DL, Seagroves TN, Slominski A (2013) Putative role of HIF transcriptional activity in melanocytes and melanoma biology. Dermatoendocrinol 5:239–251CrossRefGoogle Scholar
  28. 28.
    Valencak J, Kittler H, Schmid K, Schreiber M, Raderer M, Gonzalez-Inchaurraga M, Birner P, Pehamberger H (2009) Prognostic relevance of hypoxia inducible factor-1alpha expression in patients with melanoma. Clin Exp Dermatol 34:e962–e964CrossRefGoogle Scholar
  29. 29.
    Hanna SC, Krishnan B, Bailey ST, Moschos SJ, Kuan PF, Shimamura T, Osborne LD, Siegel MB, Duncan LM, O’Brien ET III, Superfine R, Miller CR, Simon MC, Wong KK, Kim WY (2013) HIF1α and HIF2α independently activate SRC to promote melanoma metastases. J Clin Invest 123:2078–2093CrossRefGoogle Scholar
  30. 30.
    Tátrai E, Bartal A, Gacs A, Paku S, Kenessey I, Garay T, Hegedűs B, Molnár E, Cserepes MT, Hegedűs Z, Kucsma N, Szakács G, Tóvári J (2017) Cell-type dependent HIF1α-mediated effects of hypoxia on proliferation, migration and metastatic potential of human tumor cells. Oncotarget 8:44498–44510CrossRefGoogle Scholar
  31. 31.
    Yeo EJ, Chun YS, Cho YS, Kim J, Lee JC, Kim MS, Park JW (2003) YC-1: a potential anticancer drug targeting hypoxia-inducible factor 1. J Natl Cancer Inst 95:516–525CrossRefGoogle Scholar
  32. 32.
    Scheuermann TH, Li Q, Ma HW, Key J, Zhang L, Chen R, Garcia JA, Naidoo J, Longgood J, Frantz DE, Tambar UK, Gardner KH, Bruick RK (2013) Allosteric inhibition of hypoxia inducible factor-2 with small molecules. Nat Chem Biol 9:271–276CrossRefGoogle Scholar

Copyright information

© Arányi Lajos Foundation 2019

Authors and Affiliations

  1. 1.National Institute of OncologyBudapestHungary
  2. 2.2nd Department of PathologySemmelweis UniversityBudapestHungary

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