Cadmium depletes cellular iron availability through enhancing ferroportin translation via iron responsive element

Abstract

Abstract. Cadmium (Cd) is a heavy metal that has detrimental effects on various organs. The widespread contamination of Cd in the environment, crops and food sources poses a severe threat to human health. Acute toxicities of Cd have been extensively investigated; however, the health impact of chronic low-dose exposure to Cd, particularly exposure under non-toxic concentrations, has yet to be elucidated. Furthermore, the toxic threshold of Cd is currently unknown. Ferroportin is the only known iron exporter in vertebrate cells, and it has an essential role in controlling iron egress from cells. To the best of our knowledge, the present study is the first to verify the regulation of ferroportin by Cd. Treatment with low-dose Cd (i.e. at sublethal concentrations, without undermining cell viability) increased the protein expression of ferroportin in macrophages, and this was associated with depleted cellular iron levels. Mechanistic investigations revealed that Cd modulated the ferroportin concentration at the translational level, via the iron responsive element located at the 5'-untranslated region of ferroportin. In conclusion, these data provide evidence for the molecular basis by which Cd alters cellular iron availability through elevating concentrations of ferroportin.

Suppression of ferroportin expression by cadmium stimulates proliferation, EMT, and migration in triple-negative breast cancer cells

“…Similar results were obtained in the preneoplastic MCF 10A breast epithelial cells (unpublished data). Contrary to this observation, in macrophages Cd up-regulated FPN expression and depleted cellular iron availability (Sun et al, 2015). The different expression patterns of FPN upon Cd treatment might be due to the different functional properties of the cell types.…”

Disruption of iron homeostasis and resultant health effects upon exposure to various environmental pollutants: A critical review

“…Meanwhile, Cd can impair erythropoietin synthesis in the kidney, resulting in an increase in hepcidin production and reduction of iron availability for erythropoiesis (Horiguchi, 2007). Our recent study found the expression levels of FPN could be up-regulated in macrophages upon exposure to sublethal Cd, and LIP was diminished (Sun et al, 2015). In another study by our group, we demonstrated that Cd could likely compete with ferrous iron to interact with the 5′-UTR iron response element of FPN's mRNA, affecting the translation of FPN (Sun et al, 2015).…”

“…Our recent study found the expression levels of FPN could be up-regulated in macrophages upon exposure to sublethal Cd, and LIP was diminished (Sun et al, 2015). In another study by our group, we demonstrated that Cd could likely compete with ferrous iron to interact with the 5′-UTR iron response element of FPN's mRNA, affecting the translation of FPN (Sun et al, 2015). Additionally, it has been suggested that Cd may regulate hepcidin-mediated iron homeostasis by inducing the secretion of IL-6 (Horiguchi et al, 2011).…”

“…Excess iron could accelerate tumor initiation and progression by enhancing the formation of free radicals, and by functioning as a necessary nutrient that fosters tumor cell proliferation as well (Torti and Torti, 2013). Moreover, recent studies by our group and others demonstrated that environmental pollutants, including PCBs, cadmium (Cd) and chlorpyrifos (CPF), could alter the expression levels of hepcidin (the central regulator of iron absorption) and ferroportin (FPN, the only regulator of iron exportation), and thus disrupt the hepcidin-FPN signaling (Qian et al, 2015;Sun et al, 2014Sun et al, , 2015L. Wang et al, 2013a).…”