title: Signaling steps in the induction of genomic damage by insulin in colon and kidney cells.
abstract: Diabetes mellitus (DM), a disease with almost 350 million people affected worldwide, will be the seventh leading cause of death by 2030. Diabetic patients develop various types of complications, among them an increased rate of malignancies. Studies reported the strong correlation between DM and several cancer types, of which colon and kidney cancers are the most common. Hyperinsulinemia, the high insulin blood level characteristic of early diabetes type 2, was identified as a risk factor for cancer development. In previous studies, we showed that an elevated insulin level can induce oxidative stress, resulting in DNA damage in colon cells in vitro and in kidney cells in vitro and in vivo. In the present study, we elucidate the signaling pathway of insulin-mediated genotoxicity, which is effective through oxidative stress induction in colon and kidney. The signaling mechanism is starting by phosphorylation of the insulin and insulin-like growth factor-1 receptors, followed by activation of phosphatidylinositide 3-kinase (PI3K), which in turn activates AKT. Subsequently, mitochondria and nicotinamide adenine dinucleotide phosphate oxidase (NADPH) isoforms (Nox1 and Nox4 in colon and kidney, respectively) are activated for reactive oxygen species (ROS) production, and the resulting excess ROS can attack the DNA, causing DNA oxidation. We conclude that hyperinsulinemia represents an important risk factor for cancer initiation or progression as well as a target for cancer prevention in diabetic patients.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, D-97078 Wuerzburg, Germany; Department of Analytical Chemistry, Faculty of Pharmacy, University of El-Minia, 61519 El-Minia, Egypt.
authors.forename: Eman Maher
authors.initials: EM
authors.lastname: Othman
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, D-97078 Wuerzburg, Germany.
authors.forename: Henning
authors.initials: H
authors.lastname: Hintzsche
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, D-97078 Wuerzburg, Germany. Electronic address: stopper@toxi.uni-wuerzburg.de.
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D003106:Colon / Q000378:metabolism / Q000473:pathology; D004249:DNA Damage / Q000235:genetics*; D003920:Diabetes Mellitus / Q000235:genetics*; D005609:Free Radicals / Q000378:metabolism / Q000633:toxicity; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006801:Humans; D007328:Insulin / Q000097:blood / Q000235:genetics*; D007668:Kidney / Q000378:metabolism / Q000473:pathology; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D018384:Oxidative Stress / Q000235:genetics*; D010766:Phosphorylation; D017526:Receptor, IGF Type 1 / Q000096:biosynthesis* / Q000235:genetics; D015398:Signal Transduction / Q000235:genetics
chemical_list: D005609:Free Radicals; D007328:Insulin; D000074624:NADPH Oxidase 1; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C402799:NOX1 protein, human; C498910:NOX4 protein, human; D017526:Receptor, IGF Type 1
keywords: Diabetes; Free radicals; Genotoxicity; Insulin; Mitochondria; NADPH oxidase