Iron: The cancer connection

Abstract

Iron plays an essential role in normal biological processes: The generation of cellular energy, oxygen transport, DNA synthesis and repair are all processes that require iron-coordinated proteins, either as elemental iron, heme or iron-sulfur clusters. As a transition metal with two major biological oxidation states, iron is also a critical intermediate in the generation of reactive oxygen species that can damage cellular structures and contribute to both aging and cancer. In this review, we focus on experimental and epidemiologic evidence that links iron and cancer, as well as strategies that have been proposed to either reduce or increase cellular iron for cancer therapy.

Keywords: Ferroportin; Ferroptosis; Iron chelator; Metastasis; Transferrin receptor.

Figure:

Examples of iron trafficking proteins altered in cancer. Small red circles represent iron. Proteins colored in orange are increased in most cancer cells when compared to non-malignant cells; proteins colored in blue are decreased. Upregulation of proteins involved in iron import, such as TFR1, DMT1 and 24p3R increase the labile iron pool; downregulation of ferritin shifts more iron to the labile iron pool; reduction of ferroportin increases iron retention by decreasing iron efflux. Hepcidin degrades ferroportin – more hepcidin is associated with decreased iron efflux. Upregulation of IRP2 is one of several mechanisms underlying these changes: IRP2 stabilizes TFR1 mRNA by binding to the 3’UTR of its mRNA; IRP2 also binds to the 5’ UTR of the ferritin and ferroportin mRNA to repress their translation. (IRP1 also functions as a translational regulator of TFR1, ferritin, and ferroportin; however it does not appear to exert a similar pro-tumorigenic effect). Ferritin consists of H and L subunits that are similarly regulated by IRP2; for simplicity these subunits are both represented as “ferritin”. Note that these changes are not observed in all cancers and are not necessarily present simultaneously.