Iron and carcinogenesis: from Fenton reaction to target genes.
Reactive oxygen species (ROS) have been shown to be associated with a wide variety of pathological phenomena such as carcinogenesis, inflammation, radiation and reperfusion injury. Iron, the most abundant transition metal ion in our body, may work as a catalyst for the generation of ROS in pathological conditions. In the past few years, there have been great advances in the understanding of iron metabolism. These include the discoveries of iron transporters and the gene responsible for hereditary hemochromatosis. Iron overload has been shown to be associated with carcinogenesis. We recently identified the major target genes (p16(INK4A) and p15(INK4B) tumor suppressor genes, which encode cyclin-dependent kinase inhibitors) in a ferric nitrilotriacetate-induced rat renal carcinogenesis model, in which the Fenton reaction is induced in the renal proximal tubules. Allelic loss of the p16 gene occurs early in carcinogenesis and specifically at the p16 loci as compared with other tumor suppressor genes. This led to the novel concept of 'genomic sites vulnerable to the Fenton reaction'. Here, recent new findings on iron metabolism are reviewed and the concept of the vulnerable sites explored. More effort to link iron metabolism with human carcinogenesis is anticipated.
Toyokuni
Shinya
S
Department of Pathology and Biology of Diseases, Graduate School of Medicine, Kyoto University, Kyoto, Japan. toyokuni@path1.med.kyoto-u.ac.jp
D000818:Animals; D002384:Catalysis; D018797:Cell Cycle Proteins / Q000235:genetics*; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics*; D005290:Ferric Compounds / Q000633:toxicity; D019942:Genes, p16; D006801:Humans; D007501:Iron / Q000378:metabolism*; D019190:Iron Overload / Q000150:complications / Q000235:genetics; D035941:Iron Regulatory Protein 1 / Q000502:physiology; D009369:Neoplasms / Q000209:etiology*; D009571:Nitrilotriacetic Acid / Q000031:analogs & derivatives* / Q000633:toxicity; D025521:Tumor Suppressor Proteins
C493966:CDKN2B protein, human; D018797:Cell Cycle Proteins; D050762:Cyclin-Dependent Kinase Inhibitor p15; D019941:Cyclin-Dependent Kinase Inhibitor p16; D005290:Ferric Compounds; D025521:Tumor Suppressor Proteins; D007501:Iron; D035941:Iron Regulatory Protein 1; D009571:Nitrilotriacetic Acid; C020326:ferric nitrilotriacetate