Role of dietary iron revisited: in metabolism, ferroptosis and pathophysiology of cancer

Abstract

Iron is the most abundant metal in the human body. No independent life forms on earth can survive without iron. However, excess iron is closely associated with carcinogenesis by increasing oxidative stress via its catalytic activity to generate hydroxyl radicals. Therefore, it is speculated that iron might play a dual role in cells, by both stimulating cell growth and causing cell death. Dietary iron is absorbed by the intestinal enterocytes in the form of ferrous ion which forms cLIP. Excess iron stored in the form of Ferritin serves as a reservoir under iron depletion conditions. Ferroptosis, is an iron-dependent non-mutational form of cell death process and is suppressed by iron-binding compounds such as deferoxamine. Blocking transferrin-mediated iron import or recycling of iron-containing storage proteins (i.e., ferritin) also attenuates ferroptosis, consistent with the iron-dependent nature of this process. Unsurprisingly, ferroptosis also plays a role in the development of cancer and maybe a beneficial strategy for anticancer treatment. Different lines of evidence suggest that ferroptosis plays a crucial role in the suppression of tumorigenesis. In this review, we have discussed the pros and cons of iron accumulation, utilization and, its role in cell proliferation, ferroptosis and pathophysiology of cancer.

Keywords: Iron; cancer; cytoplasmic labile iron pool (cLIP); ferroptosis; reactive oxygen species.

Figure 1

Iron import, regulation and export. Organic and inorganic iron enters into the intestinal duodenal cell through their respective ion channels in ferrous form. In the cytoplasm the ferrous ions gather together to form an iron pool called the cytoplasmic labile pool (cLIP). Depending upon the requirement cLIP will be utilized by different organelles and the extra ferrous iron is stored in ferritin. Ferrous iron cannot be transported and hence it should be reduced to ferric iron which can be transported into the circulation and is reached to other cells through a ferric ion exporter.

Figure 2

Mechanism of Ferroptosis Inhibition. SLC7A11 gene is a sodium-dependent antiporter responsible for Glutathione synthesis. The gene encodes a xCT system which imports one Cystine molecule by simultaneous export of Glutamate molecule. The transporter activity of SLC7A11 gene is stabilised by a chaperon encoded by SLC3A2 gene. Once cystine enter into the cytoplasm of the cell it is reduced to cysteine and contributes to the formation of Glutathione with Glycine and Glutamate. The Glutathione serves as a co-factor for the enzyme GPX-4 which inhibits the formation of lipid peroxides there by protecting the cells from ferroptosis and permitting cell proliferation.