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Soluble nickel interferes with cellular iron homeostasis

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Abstract

Soluble nickel compounds are likely human carcinogens. The mechanism by which soluble nickel may contribute to carcinogenesis is unclear, though several hypotheses have been proposed. Here we verify the ability of nickel to enter the cell via the divalent metal ion transporter 1 (DMT1) and disturb cellular iron homeostasis. Nickel may interfere with iron at both an extracellular level, by preventing iron from being transported into the cell, and at an intracellular level, by competing for iron sites on enzymes like the prolyl hydroxylases that modify hypoxia inducible factor-1α (HIF-1α). Nickel was able to decrease the binding of the Von Hippel–Lindau (VHL) protein to HIF-1α, indicating a decrease in prolyl hydroxylase activity. The ability of nickel to affect various iron dependent processes may be an important step in nickel dependent carcinogenesis. In addition, understanding the mechanisms by which nickel activates the HIF-1α pathway may lead to new molecular targets in fighting cancer.

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References

  1. International Agency for Research on Cancer I: Monographs on the Evaluation of Carcinogenic Risks to Humans: Chromium Nickel and Welding. Lyon, France, 1990

  2. Kasprzak KS, Sunderman FW, Jr., Salnikow K: Nickel carcinogenesis. Mutat Res 533: 67–97, 2003

    PubMed  Google Scholar 

  3. McEwan JC: Cytological monitoring of nickel sinter plant workers. Ann NY Acad Sci 271: 365–369, 1976

    PubMed  Google Scholar 

  4. Roberts RS, Julian JA, Muir DC, Shannon HS: Cancer mortality associated with the high-temperature oxidation of nickel subsulfide. IARC Sci Publ, Vol. 53: 23–35, 1984

    Google Scholar 

  5. Costa M, Sutherland JE, Peng W, Salnikow K, Broday L, Kluz T: Molecular biology of nickel carcinogenesis. Mol Cell Biochem 222: 205–211, 2001

    PubMed  Google Scholar 

  6. Anttila A, Pukkala E, Aitio A, Rantanen T, Karjalainen S: Update of cancer incidence among workers at a copper/nickel smelter and nickel refinery. Int Arch Occup Environ Health 71: 245–250, 1998

    PubMed  Google Scholar 

  7. Grimsrud TK, Berge SR, Haldorsen T, Andersen A: Exposure to different forms of nickel and risk of lung cancer. Am J Epidemiol 156: 1123–1132, 2002

    Article  PubMed  Google Scholar 

  8. Grimsrud TK, Berge SR, Martinsen JI, Andersen A: Lung cancer incidence among Norwegian nickel-refinery workers 1953–2000. J Environ Monit 5: 190–197, 2003

    Article  PubMed  Google Scholar 

  9. Gunshin H, Mackenzie B, Berger UV, Gunshin Y, Romero MF, Boron WF, Nussberger S, Gollan JL, Hediger MA: Cloning and characterization of a mammalian proton-coupled metal-ion transporter. Nature 388: 482–488, 1997

    Article  PubMed  Google Scholar 

  10. Garrick MD, Dolan KG, Horbinski C, Ghio AJ, Higgins D, Porubcin M, Moore EG, Hainsworth LN, Umbreit JN, Conrad ME, Feng L, Lis A, Roth JA, Singleton S, Garrick LM: DMT1: A mammalian transporter for multiple metals. BioMetals 16: 41–54, 2003

    Article  PubMed  Google Scholar 

  11. Farcich EA, Morgan EH: Uptake of transferrin-bound and nontransferrin-bound iron by reticulocytes from the Belgrade laboratory rat: comparison with Wistar rat transferrin and reticulocytes. Am J Hematol 39: 9–14, 1992

    PubMed  Google Scholar 

  12. Garrick LM, Dolan KG, Romano MA, Garrick MD: Non-transferrin-bound iron uptake in Belgrade and normal rat erythroid cells. J Cell Physiol 178: 349–358, 1999

    PubMed  Google Scholar 

  13. Chen H, Davidson T, Singleton S, Garrick MD, Costa M: Nickel decreases cellular iron level and converts cytosolic aconitase to iron-regulatory protein 1 in A549 cells. Toxicol Appl Pharmacol, in press.

  14. Epstein AC, Gleadle JM, McNeill LA, Hewitson KS, O'Rourke J, Mole DR, Mukherji M, Metzen E, Wilson MI, Dhanda A, Tian YM, Masson N, Hamilton DL, Jaakkola P, Barstead R, Hodgkin J, Maxwell PH, Pugh CW, Schofield CJ, Ratcliffe PJ: C. elegans EGL-9 and mammalian homologs define a family of dioxygenases that regulate HIF by prolyl hydroxylation. Cell 107: 43–54, 2001

    Article  PubMed  Google Scholar 

  15. Jaakkola P, Mole DR, Tian YM, Wilson MI, Gielbert J, Gaskell SJ, Kriegsheim A, Hebestreit HF, Mukherji M, Schofield CJ, Maxwell PH, Pugh CW, Ratcliffe PJ: Targeting of HIF-alpha to the von Hippel-Lindau ubiquitylation complex by O2-regulated prolyl hydroxylation. Science 292: 468–472, 2001

    PubMed  Google Scholar 

  16. Lando D, Peet DJ, Whelan DA, Gorman JJ, Whitelaw ML: Asparagine hydroxylation of the HIF transactivation domain a hypoxic switch. Science 295: 858–861, 2002

    Article  PubMed  Google Scholar 

  17. Salnikow K, Davidson T, Costa M: The role of hypoxia-inducible signaling pathway in nickel carcinogenesis. Environ Health Perspect 110: 831–834, 2002

    PubMed  Google Scholar 

  18. Semenza GL: HIF-1 and human disease: one highly involved factor. Genes Dev 14: 1983–1991, 1983

    Google Scholar 

  19. Maxwell PH, Ratcliffe PJ: Oxygen sensors and angiogenesis. Semin Cell Dev Biol 13: 29–37, 2002

    Article  PubMed  Google Scholar 

  20. Wiesener MS, Maxwell PH: HIF and oxygen sensing: as important to life as the air we breathe? Ann Med 35: 183–190, 2003

    Google Scholar 

  21. D'Angelo G, Duplan E, Boyer N, Vigne P, Frelin C: Hypoxia up-regulates prolyl hydroxylase activity: a feedback mechanism that limits HIF-1 responses during reoxygenation. J Biol Chem 278: 38183–38187, 2003

    Article  PubMed  Google Scholar 

  22. Knopfel M, Zhao L, Garrick MD: Transport of divalent transition-metal ions is lost in small-intestinal tissue of b/b Belgrade rats. Biochemistry 44(9): 3454–3465, 2005

    Article  PubMed  Google Scholar 

  23. Maxwell P, Salnikow K: HIF-1: an oxygen and metal responsive transcription factor. Cancer Biol Ther 3: 29–35, 2004

    PubMed  Google Scholar 

  24. Batie CJ, Ballou DP: Phthalate dioxygenase. Meth Enzymol 188: 61–70, 1990

    PubMed  Google Scholar 

  25. Batie CJ, LaHaie E, Ballou DP: Purification and characterization of phthalate oxygenase and phthalate oxygenase reductase from Pseudomonas cepacia. J Biol Chem 262: 1510–1518, 1987

    PubMed  Google Scholar 

  26. Oshiro S, Nozawa K, Hori M, Zhang C, Hashimoto Y, Kitajima S, Kawamura K: Modulation of iron regulatory protein-1 by various metals. Biochem Biophys Res Commun 290: 213–218, 2002

    PubMed  Google Scholar 

  27. Salnikow K, Donald SP, Bruick RK, Zhitkovich A, Phang JM, Kasprzak KS: Depletion of intracellular ascorbate by the carcinogenic metals nickel and cobalt results in the induction of hypoxic stress. J Biol Chem 279: 40337–40344, 2004

    PubMed  Google Scholar 

  28. Bridges KR, Hoffman KE: The effects of ascorbic acid on the intracellular metabolism of iron and ferritin. J Biol Chem 261: 14273–14277, 1986

    PubMed  Google Scholar 

  29. Toth I, Rogers JT, McPhee JA, Elliott SM, Abramson SL, Bridges KR: Ascorbic acid enhances iron-induced ferritin translation in human leukemia and hepatoma cells. J Biol Chem 270: 2846–2852, 1995

    Article  PubMed  Google Scholar 

  30. Toth I, Bridges KR: Ascorbic acid enhances ferritin mRNA translation by an IRP/aconitase switch. J Biol Chem 270: 19540–19544, 1995

    Article  PubMed  Google Scholar 

  31. Hanahan D, Folkman J: Patterns and emerging mechanisms of the angiogenic switch during tumorigenesis. Cell 86: 353–364, 1996

    Article  PubMed  Google Scholar 

  32. Erez N, Milyavsky M, Eilam R, Shats I, Goldfinger N, Rotter V: Expression of prolyl-hydroxylase-1 (PHD1/EGLN2) suppresses hypoxia inducible factor-1alpha activation and inhibits tumor growth. Cancer Res 63: 8777–8783, 2003

    PubMed  Google Scholar 

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Authors and Affiliations

  1. Nelson Institute of Environmental Medicine, School of Medicine, New York University, Tuxedo, New York, USA

    Todd Davidson, Haobin Chen & Max Costa

  2. Department of Biochemistry, SUNY, Buffalo, New York, USA

    Michael D. Garrick

  3. Neurobiologie Vasculaire, INSERM U615, Université de Nice Sophia Antipolis, Parc, Valrose, Nice, France

    Gisela D'Angelo

  4. Nelson Institute of Environmental Medicine, School of Medicine, New York University, 57 Old Forge Road, Tuxedo, NY, 10987, USA

    Max Costa

Authors
  1. Todd Davidson
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  2. Haobin Chen
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  3. Michael D. Garrick
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  4. Gisela D'Angelo
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  5. Max Costa
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Correspondence to Max Costa.

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Davidson, T., Chen, H., Garrick, M.D. et al. Soluble nickel interferes with cellular iron homeostasis. Mol Cell Biochem 279, 157–162 (2005). https://doi.org/10.1007/s11010-005-8288-y

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  • DOI: https://doi.org/10.1007/s11010-005-8288-y

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