Revised model for cell cycle regulation by iron: differential roles between transferrin and ferritin

Iron is essential for neoplasms including natural killer (NK) cell lymphoma, and mainly supplemented by transferrin and stored by ferritin. Although accumulating studies had demonstrated that iron chelation arrests cell cycle progression at G1 phase, our previous studies showed the induction of DNA double strand break at S phase cell cycle without G1 arrest by selective inhibition of cellular transferrin uptake, indicating that the existence of some undiscovered differences in the roles of the two major iron sources for cell cycle regulation. In this study, we identified a novel cell cycle regulation of transferrin binding iron in NK cell lymphoma. Blocking transferrin uptake induced S phase arrest owing to the dysfunction of nascent DNA synthesis. Moreover, canonical G1 arrest was observed with mitochondrial dysfunction followed by downregulation of mTORC1 and dephosphorylation of Rb only when intracellular iron storage was deprived by iron chelation. These results suggested that iron is critically involved in at least two steps of the cell cycle: the S phase and G1/S transition. Especially, considering the toxicity of mitochondrial dysfunction to normal cells and cell cycle dependent manner of S phase-specific DNA damage due to selective inhibition of transferrin uptake, transferrin receptor blockers are thought to be more suitable than iron chelators as antineoplastic agents. Overall, the current canonical model of cell cycle regulation by iron requires revision.