Krebswissenschaft und -therapie

Preferential Localization of Iron in The Chromatin of Fe-Enriched Cells Is Linked to DNA Cleavage Sites and Control of Carcinogenesis

Abstract

Clelia Rejane Antonio Bertoncini, Rogerio Meneghini, Fernando Galembeck, Michele Longoni Calió, Adriana Ferraz Carbonel and Rodrigo Aquino de Castro

DNA oxidation by oxygen-radicals generated via an iron catalyzed Fenton reaction has been extensively investigated, but little is known about iron localization in the nuclei of mammalian cells. In vitro studies showed the presence of five oxygen and one nitrogen atoms in the inner coordination sphere of the Fe(II)-DNA complex using X-ray absorption spectroscopy (XANES and EXAFS). The identification of ferritin in the nucleus of cultured cells, as well as iron-protein receptors in the nuclear membrane suggests that iron is actively transported into the nucleus. Therefore, pictures from energy-loss spectroscopic imaging (ESI) are included in this mini-review to illustrate the distribution of iron in a fibroblast cell line. These fibroblasts were iron-overloaded by being cultured in a medium containing Fe(III)-nitrilotriacetate (FeNTA). The elemental mapping of iron and phosphorus was coincident in ultrastructures and revealed a significant concentration of both in condensed chromatin; by contrast, the elemental mapping of nitrogen, used as a control, revealed a homogenous distribution across the entire cell. This observed preferential localization was surprising, considering the pro-oxidant status of iron and the importance of maintaining genome integrity. Interestingly, recent published works demonstrates that iron chelators such as genistein and daidzein, derived from soy isoflavones, can attenuate the expression of genes related to increased cancer risk and oxidative damage in the reproductive tract of female mice. In this same sense, mesenchymal stem cells also exhibit antioxidant properties by reducing superoxide, lipid peroxidation, and DNA breaks to healthful levels after transplantation into the brains of stroke prone spontaneously hypertensive rats. Therefore, we bring attention to the use of all potential antioxidants, particularly those with affinity for both iron and DNA, in therapies for several diseases.