Soluble nickel inhibits HIF-prolyl-hydroxylases creating persistent hypoxic signaling in A549 cells

Molecular Carcinogenesis
Todd L DavidsonMax Costa

Abstract

Soluble nickel compounds are carcinogenic to humans although the mechanism by which they cause cancer remains unclear. One major consequence of exposure to nickel is the stabilization of hypoxia inducible factor-1alpha (HIF-1alpha), a protein known to be overexpressed in a variety of cancers. In this study, we report a persistent stabilization of HIF-1alpha by nickel chloride up to 72 h after the removal of nickel from the culture media. In addition, we show that the HIF-prolyl hydroxylases (PHD's) are inhibited when cells are exposed to nickel and that they remain repressed for up to 72 h after nickel is removed. We then show that nickel can inhibit purified HIF-PHD's 2 in vitro, through direct interference with the enzyme. Through theoretical calculations, we also demonstrate that nickel may be able to replace the iron in the active site of this enzyme, providing a plausible mechanism for the persistent inhibition of HIF-PHD's by nickel. The data presented suggest that nickel can interfere with HIF-PHD directly and does not inhibit the enzyme by simply depleting cellular factors, such as iron or ascorbic acid. Understanding the mechanisms by which nickel can inhibit HIF-PHD's and stabilize HIF-1alpha may be important in the t...Continue Reading

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Citations

Jan 1, 2009·Metallomics : Integrated Biometal Science·Adriana Arita, Max Costa
Apr 5, 2012·Metallomics : Integrated Biometal Science·Yana ChervonaMax Costa
Sep 17, 2009·Antioxidants & Redox Signaling·Simon NagelChristopher J Schofield
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May 1, 2009·Toxicological Sciences : an Official Journal of the Society of Toxicology·Antonia A Nemec, Aaron Barchowsky
Aug 11, 2011·Toxicological Sciences : an Official Journal of the Society of Toxicology·Jodie R PietruskaAgnes B Kane
May 2, 2006·Molecular and Cellular Biology·Haobin ChenMax Costa
Jun 10, 2009·Cancer Epidemiology, Biomarkers & Prevention : a Publication of the American Association for Cancer Research, Cosponsored by the American Society of Preventive Oncology·Jin DingHongyang Wang
Dec 20, 2008·Biometals : an International Journal on the Role of Metal Ions in Biology, Biochemistry, and Medicine·Haobin Chen, Max Costa
Apr 2, 2016·Current Pharmacology Reports·Lakshmanan JagannathanMax Costa
Jan 27, 2015·Toxicology and Applied Pharmacology·Robert M HarrisNikolas J Hodges
Jul 31, 2012·Free Radical Biology & Medicine·Yana Chervona, Max Costa
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Jul 17, 2020·Carcinogenesis·Yusha Zhu, Max Costa
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Jul 10, 2019·Mutagenesis·Alanna R Kaplan, Peter M Glazer
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