B109
Induction in iron transport proteins is downstream of iron mediated Wnt signalling
Matthew Brookes, Keith Roberts, Tariq Iqbal, Chris Tselepis
University of Birmingham, Birmingham, UK
Background
Excess cellular iron is considered a pro-carcinogen in colorectal carcinogenesis. In particular it has been reported that transferrin receptor (TfR1) and Divalent metal transporter (DMT1), the main proteins involved in cellular iron acquisition are over expressed in cancer despite high tissue iron. In contrast in non-cancer lineages high iron results in a repression in iron import machinery. The aim of this study was to determine if iron-mediated Wnt signalling which has recently been reported could impact on the expression of iron transport proteins.
Method
qRT-PCR and western blotting was employed to assess expression of TfR1, DMT1, ferritin and c-myc. To assess the importance of APC full length APC was reconstituted into SW480 cells +/- iron (either as hemin (50uM) or iron sulphate (100uM)).
Results
Culturing RKO cells (wild type-APC) with iron resulted in a repression in TfR1 and DMT1, whilst in SW480 cells culture with iron mediated inductions in both proteins. The latter could be completely reversed by transfection of wild type APC, implying that iron mediated Wnt signalling can promote the expression of TfR1 and DMT1. To determine if these effects were mediated through the Wnt target c-myc, c-myc was induced in wild type APC cells. C-myc induction resulted in increased TfR1 and DMT1 expression which could be amplified by iron.
Conclusion
Iron mediated Wnt signalling through c-myc can further promote the expression of the iron import proteins creating a positive feedback loop. Blocking c-myc expression may provide a mechanism of preventing the accumulation of iron in cancer.
