Ferritin Heavy Chain: From Redox Cycling to Cancer Biology

Iron is an essential nutrient for physiological cellular functions: as cofactor for key enzymes, it is involved in DNA duplication and repair thus representing a key element for cell replication, metabolism and growth. Due to its main role in iron storage, ferritin has been largely referred as redox-related protein for many years. However, increasing evidences suggest that perturbations of intracellular steady state amount of ferritin, and particularly of its heavy subunit (FHC), are key events in the pathogenesis of cancer initiation and progression. In the past decade many studies have demonstrated that FHC participates in cancer related pathways such as growth suppressor evasion, angiogenesis, epithelial to mesenchymal transition (EMT), dysregulation of chemokine signalling and enhanced stem cell expansion. The molecular mechanisms whereby FHC exerts these activities are either iron-dependent or ironindependent. Among the latters, the ability to regulate critical oncogenes (c-myc, NF-kB) or tumor suppressors (p53) as well as to modulate oncomiRNAs expression and chemokine signalling (CXCR4) strongly suggests that FHC is a much more versatile protein than simply iron storage. The deep understanding of these novel and still not completely characterized functions, as well as the discovery of other potential properties, position ferritin as a promising target in cancer therapy.