Research Papers:

Ferric citrate and ferric EDTA but not ferrous sulfate drive amphiregulin-mediated activation of the MAP kinase ERK in gut epithelial cancer cells

Nathalie M. Scheers _, Dora I.A. Pereira, Nuno Faria and Jonathan J. Powell

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Oncotarget. 2018; 9:17066-17077. https://doi.org/10.18632/oncotarget.24899

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Nathalie M. Scheers1,2, Dora I.A. Pereira2,3,4, Nuno Faria2,5 and Jonathan J. Powell2,5

1Department of Biology and Biological Engineering, Chalmers University of Technology, Gothenburg, Sweden

2Elsie Widdowson Laboratory, Medical Research Council, Cambridge, UK

3Department of Pathology, University of Cambridge, Cambridge, UK

4MRC Unit The Gambia at the London School of Hygiene & Tropical Medicine, Fajara, Banjul, The Gambia

5Biomineral Research Group, Department of Veterinary Medicine, University of Cambridge, Cambridge, UK

Correspondence to:

Nathalie M. Scheers, email: [email protected]

Keywords: iron; ferric citrate; ferric EDTA; amphiregulin; pERK

Received: November 30, 2017    Accepted: March 09, 2018    Published: March 30, 2018


Ferric chelates may be used as oral iron supplements or phosphate binders but both ferric citrate and ferric EDTA have been shown to promote tumor burden in murine models of colon cancer. Here we studied their effects on cancer cell growth, at typical supplemental iron levels encountered in the gastrointestinal tract (0.01-0.2 mM). Caco-2 and/or Hutu-80 cells were exposed to these forms of chelated iron or to ferrous sulfate and outcomes were assessed using cell proliferation assays, proteome profiler arrays, western blot, and ELISA. Ferric EDTA and ferric citrate increased cellular levels of the onco-protein amphiregulin and its receptor (EGFr) which in turn stimulated the activation of the MAP kinase ERK. Simultaneously, the expression of the negative Wnt regulator, DKK-1, increased suggesting that cell proliferation through the Wnt pathway may be less pronounced in the presence of ferric EDTA and ferric citrate, unlike for ferrous sulfate. Moreover, ferrous sulfate did not increase levels of cellular amphiregulin or EGFr. We conclude that specific iron compounds affect cell signaling differently and some may increase the risk of colon cancer advancement in an amphiregulin-dependent fashion. Further scrutiny of safe oral iron use is merited.

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