Selective Inhibition of HIF1α Expression by ZnSO4 Has Antitumoral Effects in Human Melanoma
- 59 Downloads
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.
KeywordsZnSO4 Human melanoma HIF1α Metastasis inhibition
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.
- 1.Vallee BL, Falchuk KH (1993) The biochemical basis of zinc physiology. Phys Rev 73:79–118Google Scholar
- 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
- 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
- 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
- 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
- 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
- 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