A role for iron in Wnt signalling

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

Expression of (Pro)renin Receptor During Rapamycin-Induced Erythropoiesis in K562 Erythroleukemia Cells and Its Possible Dual Actions on Erythropoiesis

“…(P)RR and v-ATPase were shown to be required to mediate Wnt signaling during antero-posterior patterning of Xenopus early central nervous system development. There has been accumulating evidence which shows the close relationship among iron, the Wnt signaling and erythropoiesis (Brookes et al 2008;Tarafdar et al 2013). Canonical Wnt/β-catenin signaling plays important roles in mesodermal specification, primitive erythropoiesis and early hematopoietic progenitor formation during hematopoietic induction (Tarafdar et al 2013).…”

“…Canonical Wnt/β-catenin signaling plays important roles in mesodermal specification, primitive erythropoiesis and early hematopoietic progenitor formation during hematopoietic induction (Tarafdar et al 2013). Brookes et al (2008) speculated that iron-medicated Wnt signaling and c-myc induced expression of transferrin receptor 1. We therefore could not deny the possibility that the Wnt/β-catenin signaling acts in cooperation with (P)RR, v-ATPase and mTORC1 in erythropoiesis.…”

Coordination compounds in cancer: Past, present and perspectives

“…Iron is involved especially in oxygen transport, DNA synthesis, oxidative phosphorylation, and cell cycle progression, and all of them have a role in carcinogenesis Brookes et al, 2008;Coombs et al, 2012). The potential cytotoxic activity of iron complexes appears to be related to the redox reactions occurring between Fe(II) and Fe(III) in physiological conditions (Jungwirth et al, 2011).…”

Increased hepcidin expression in colorectal carcinogenesis

“…In the background of an elevation in the cellular iron import proteins such as transferrin receptor 1 and Divalent metal transporter 1, this culminates in cellular iron accumulation; a phenotype which we have previously reported in colorectal cancer [14] . Furthermore, we have recently demonstrated that elevating intracellular iron in the presence of mutations in either adenomatous polyposis coli (APC) or β-catenin results in increased Wnt signalling; the major oncogenic signalling pathway in the colon [9,10] . Thus hepcidin expression at the level of the tumour may be a mechanism of ultimately accentuating carcinogenesis and that abrogating hepcidin expression either directly or indirectly through IL-6 may provide a strategy for therapeutic intervention.…”

“…Increased hepcidin levels are likely to also cause an accumulation of iron in other ferroportin expressing cell lineages such as colonocytes. Our recent studies have shown that raising colonocyte iron levels can result in increased Wnt signalling which has been shown to be crucial in colorectal carcinogenesis [9,10] . However, to date there are no studies addressing whether hepcidin expression contributes to the anaemia in colorectal cancer and whether hepcidin itself may be considered a pro-oncogenic factor.…”