Iron and cancer: recent insights

Abstract

Iron is an essential dietary element. However, the ability of iron to cycle between oxidized and reduced forms also renders it capable of contributing to free radical formation, which can have deleterious effects, including promutagenic effects that can potentiate tumor formation. Dysregulation of iron metabolism can increase cancer risk and promote tumor growth. Cancer cells exhibit an enhanced dependence on iron relative to their normal counterparts, a phenomenon we have termed iron addiction. Work conducted in the past few years has revealed new cellular processes and mechanisms that deepen our understanding of the link between iron and cancer. Control of iron efflux through the combined action of ferroportin, an iron efflux pump, and its regulator hepcidin appears to play an important role in tumorigenesis. Ferroptosis is a form of iron-dependent cell death involving the production of reactive oxygen species. Specific mechanisms involved in ferroptosis, including depletion of glutathione and inhibition of glutathione peroxidase 4, have been uncovered. Ferritinophagy is a newly identified mechanism for degradation of the iron storage protein ferritin. Perturbations of mechanisms that control transcripts encoding proteins that regulate iron have been observed in cancer cells, including differences in miRNA, methylation, and acetylation. These new insights may ultimately provide new therapeutic opportunities for treating cancer.

Keywords: cancer; ferritinophagy; ferroptosis; iron.

Figure 1

Overview of iron absorption and metabolism. Enterocytes absorb dietary iron through the combined action of ferric reductases, such as Dcytb and divalent metal transporter DMT1. Ferrous iron taken up by enterocytes is exported into the circulation by ferroportin (FPN-1). Concurrently, the Fe²⁺ is oxidized to Fe³⁺ by hephaestin (HEPH), which is functionally associated with FPN-1. Fe³⁺ is loaded on to circulating apo-TF in plasma. Cells take up diferric TF through the cell surface transferrin receptor (TFR1). The TFR1–TF–(Fe⁺³)₂ complex is endocytosed, and iron is released from TF. Fe³⁺ is reduced by the ferric reductase STEAP3, and Fe²⁺ is then transported to the cytosol by DMT1, where it enters the cytosolic labile iron pool (LIP). The LIP is utilized by cells for various metabolic needs. Excess iron is stored in ferritin or effluxed to the circulation through FPN-1. Hepatocytes synthesize hepcidin (HAMP) in response to systemic iron levels; the binding of hepcidin to FPN-1 triggers FPN-1 degradation, thus inhibiting iron efflux.

Figure 2

Overview of ferroptosis. Ferroptosis is an iron (Fe)-dependent form of cell death involving the generation of reactive oxygen species (ROS) and lipid peroxides (LOOH). ROS formation is promoted by Fe, NADPH oxidase 1 (NOX1), and the ferroptosis inducer (Fin) sorafenib. ROS formation, and therefore ferroptosis, is reduced by iron chelators, heat shock protein β-1 (HSPB1), ferrostatin, ferrostatin and artemisinin derivatives, and antioxidants. Glutathione (GSH) is an antioxidant particularly important in protecting cells from ferroptosis. GSH is a necessary cofactor for glutathione-dependent peroxidase 4 (GPX4), which reduces LOOH to benign lipid alcohols (LOH), oxidizing GSH to glutathione disulfide (GSSG) in the process. GPX4 is the master regulator of ferroptosis, protecting cells from ferroptotic cell death. Class 2 ferroptosis inducers directly inhibit GPX4 function while class 1 ferroptosis inducers reduce GSH availability. GSH synthesis is limited by the availability of cystine. Cystine is imported into cells though the system X_c⁻ cystine/glutamate antiporter, reduced to two cysteines, and converted GSH. Several class 1 ferroptosis inducers, as well as p53 and sorafenib, inhibit the function of system X_c⁻.