1. ¹CRUK Institute for Cancer Studies, University of Birmingham, Birmingham, UK
2. ²City Hospital, Birmingham, UK
3. ³School of Biosciences, University of Birmingham, Birmingham, UK
4. ⁴Division of Medical Sciences, University of Birmingham, Birmingham, UK

Correspondence: Dr C Tselepis, CRUK Institute for Cancer Studies, University of Birmingham, Vincent Drive, Edgbaston, Birmingham, B32 1NX, UK. E-mail: c.tselepis@bham.ac.uk

⁵These two authors contributed equally to this work.

Received 15 January 2007; Revised 15 June 2007; Accepted 6 July 2007; Published online 13 August 2007.

Abstract

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) containing 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 -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 -catenin, was also responsive suggesting that the role of iron is to regulate -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.