Linking Cancer Metabolic Dysfunction and Genetic Instability through the Lens of Iron Metabolism

Abstract

Iron (Fe) is an essential element that plays a fundamental role in a wide range of cellular functions, including cellular proliferation, DNA synthesis, as well as DNA damage and repair. Because of these connections, iron has been strongly implicated in cancer development. Cancer cells frequently have changes in the expression of iron regulatory proteins. For example, cancer cells frequently upregulate transferrin (increasing uptake of iron) and down regulate ferroportin (decreasing efflux of intracellular iron). These changes increase the steady-state level of intracellular redox active iron, known as the labile iron pool (LIP). The LIP typically contains approximately 2% intracellular iron, which primarily exists as ferrous iron (Fe²⁺). The LIP can readily contribute to oxidative distress within the cell through Fe²⁺-dioxygen and Fenton chemistries, generating the highly reactive hydroxyl radical (HO^•). Due to the reactive nature of the LIP, it can contribute to increased DNA damage. Mitochondrial dysfunction in cancer cells results in increased steady-state levels of hydrogen peroxide and superoxide along with other downstream reactive oxygen species. The increased presence of H₂O₂ and O₂^•- can increase the LIP, contributing to increased mitochondrial uptake of iron as well as genetic instability. Thus, iron metabolism and labile iron pools may play a central role connecting the genetic mutational theories of cancer to the metabolic theories of cancer.

Keywords: cancer; ferritin; genetic instability; genetic theory of cancer; iron metabolism; labile iron pool; metabolism; mitochondria; mitochondrial iron; transferrin receptors.

Figure 1

Simplified model of the network for intracellular iron regulation. This model unifies the genetic and metabolic theories of cancer where the intracellular labile iron pool (LIP) acts as a central hub in the genesis of cancer thereby linking iron metabolism to traditional hallmarks of cancer.

Figure 2

Alterations in iron uptake and efflux in cancer cells compared to normal cells. Cancer cells often exhibit increased expression of TfR that can increase iron uptake as well as increased hepcidin leading to degradation of FPN-1, thereby limiting export of iron from the cell. To facilitate increased uptake of iron, cancer cells have also been shown to increase expression of V-ATPase and STEAP3, which are important for the endosomal internalization of the di-ferric Tf-TfR complex and facilitation of the release of ferrous iron into the cytosol.

Figure 3

Potential consequences from overexpression of ferritin in cancer cells. Ferritin holds iron that can be labilized by increased levels of ROS generated by mitochondria. This “liberated” iron could be taken up by mitochondria to support proliferation. At the same time, ferritin could act in a signaling capacity by increasing expression of the promitotic, oncogenic transcription factor, FoxM1.