Cancer cell death induced by ferritins and the peculiar role of their labile iron pool

// Juan Carlos Cutrin 1 , Diego Alberti 1 , Caterina Bernacchioni 2 , Silvia Ciambellotti 2 , Paola Turano 2 , Claudio Luchinat 2 , Simonetta Geninatti Crich 1 and Silvio Aime 2, 3 1 University of Torino, Department of Molecular Biotechnology and Health Sciences, Torino, Italy 2 Center for Magnetic Resonance, University of Florence, Florence, Italy 3 IBB-CNR, Sede Secondaria c/o MBC, Torino, Italy Correspondence to: Simonetta Geninatti Crich, email: simonetta.geninatti@unito.it Claudio Luchinat, email: luchinat@cerm.unifi.it Keywords: ferritin; iron release; cancer therapy; HeLa cells; TFR1 Received: May 04, 2017      Accepted: April 28, 2018      Published: June 15, 2018 ABSTRACT Cellular uptake of human H-ferritin loaded with 50 or 350 iron ions results in significant cytotoxicity on HeLa cells at submicromolar concentrations. Conversely, Horse Spleen Ferritin, that can be considered a model of L-cages, as it contains only about 10% of H subunits, even when loaded with 1000 iron ions, is toxic only at >1 order of magnitude higher protein concentrations. We propose here that the different cytotoxicity of the two ferritin cages originates from the presence in H-ferritin of a pool of non-biomineralized iron ions bound at the ferroxidase catalytic sites of H-ferritin subunits. This iron pool is readily released during the endosomal-mediated H-ferritin internalization.