A role for iron in Wnt signalling.pdf

ORIGINAL ARTICLE A role for iron in Wnt signalling MJ Brookes1,2, J Boult1, K Roberts1, BT Cooper2, NA Hotchin3, G Matthews4, T Iqbal1,5 and C Tselepis1,5 1CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK; 2City Hospital, Birmingham, UK; 3School of Biosciences, University of Birmingham, Birmingham, UK and 4Division of Medical Sciences, University of Birmingham, Birmingham, UK There is an emerging body of evidence implicating iron in carcinogenesis and in particular colorectal cancer, but whether this involves Wnt signalling, a major oncogenic signalling pathway has not been studied. We aimed to determine the effect of iron loading on Wnt signalling using mutant APC (Caco-2 and SW480) and wild-type APC (HEK-293 and human primary fibroblasts) contain- ing cell lines. Elevating cellular iron levels in Caco-2 and SW480 cells caused increased Wnt signalling as indicated by increased TOPFLASH reporter activity, increased mRNA expression of two known targets, c-myc and Nkd1, and increased cellular proliferation. In contrast wild-type APC and b-catenin-containing lines, HEK 293 and human primary fibroblasts were not responsive to iron loading. This was verified in SW480 cells that no longer induced iron-mediated Wnt signalling when transfected with wild-type APC. The cell line LS174T, wild type for APC but mutant for b-catenin, was also responsive suggesting that the role of iron is to regulate b-catenin. Furthermore, we show that E-cadherin status has no influence on iron-mediated Wnt signalling. We thus speculate that excess iron could exacerbate tumorigenesis in the background of APC loss, a common finding in cancers. Oncogene (2008) 27, 966–975; doi:10.1038/sj.onc.1210711; published online 13 August 2007 Keywords: Wnt; E-cadherin; iron; colon Introduction Aberrant activation of Wnt signalling represents a major oncogenic process integral to the evolution and devel- opment of many epithelial cancers including cancers of the gastrointestinal (GI