Iron chelators with high antiproliferative activity up-regulate the expression of a growth inhibitory and metastasis suppressor gene: a link between iron metabolism and proliferation

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Abstract
Iron (Fe) is critical for proliferation, but its precise role in cell cycle progression remains unclear. In this study, we examined the mechanisms involved by assessing the effects of Fe chelators on the expression of molecules that play key roles in this process. In initial studies, gene arrays were used to assess gene expression after incubating cells with 2 Fe chelators, namely, desferrioxamine (DFO) and 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), or the DNA-damaging agent, actinomycin D. From the genes assessed, only the N-myc downstream-regulated gene 1 (Ndrg1) was specifically up-regulated by Fe chelation. Although the function of Ndrg1 is unclear, previous studies showed it markedly slows tumor growth and acts as a potent metastasis suppressor. Incubation of cells with chelators markedly increased Ndrg1 mRNA and protein expression, but this was not found with their Fe complexes or when the Fe-binding site had been inactivated. Increased Ndrg1 expression following Fe chelation was related to the permeability and antiproliferative activity of chelators and could be reversed by Fe repletion. Moreover, Ndrg1 up-regulation after chelation occurred at the transcriptional level and was mediated by hypoxia inducible factor-1α (HIF-1α)-dependent and -independent mechanisms. Our investigation suggests Ndrg1 is a novel link between Fe metabolism and the control of proliferation.

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