title: Role of PTEN in Oxidative Stress and DNA Damage in the Liver of Whole-Body Pten Haplodeficient Mice.
abstract: Type 2 diabetes (T2DM) and obesity are frequently associated with non-alcoholic fatty liver disease (NAFLD) and with an elevated cancer incidence. The molecular mechanisms of carcinogenesis in this context are only partially understood. High blood insulin levels are typical in early T2DM and excessive insulin can cause elevated reactive oxygen species (ROS) production and genomic instability. ROS are important for various cellular functions in signaling and host defense. However, elevated ROS formation is thought to be involved in cancer induction. In the molecular events from insulin receptor binding to genomic damage, some signaling steps have been identified, pointing at the PI3K/AKT pathway. For further elucidation Phosphatase and Tensin homolog (Pten), a tumour suppressor phosphatase that plays a role in insulin signaling by negative regulation of PI3K/AKT and its downstream targets, was investigated here. Dihydroethidium (DHE) staining was used to detect ROS formation in immortalized human hepatocytes. Comet assay and micronucleus test were performed to investigate genomic damage in vitro. In liver samples, DHE staining and western blot detection of HSP70 and HO-1 were performed to evaluate oxidative stress response. DNA double strand breaks (DSBs) were detected by immunohistostaining. Inhibition of PTEN with the pharmacologic inhibitor VO-OHpic resulted in increased ROS production and genomic damage in a liver cell line. Knockdown of Pten in a mouse model yielded increased oxidative stress levels, detected by ROS levels and expression of the two stress-proteins HSP70 and HO-1 and elevated genomic damage in the liver, which was significant in mice fed with a high fat diet. We conclude that PTEN is involved in oxidative stress and genomic damage induction in vitro and that this may also explain the in vivo observations. This further supports the hypothesis that the PI3K/AKT pathway is responsible for damaging effects of high levels of insulin.
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Ezgi Eyluel
authors.initials: EE
authors.lastname: Bankoglu
authors.affiliation: Clinic for Endocrinology & Diabetology, University Hospital Zuerich, Zuerich, Switzerland.
authors.forename: Oliver
authors.initials: O
authors.lastname: Tschopp
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Schmitt
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Philipp
authors.initials: P
authors.lastname: Burkard
authors.affiliation: Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Daniel
authors.initials: D
authors.lastname: Jahn
authors.affiliation: Clinic for Endocrinology & Diabetology, University Hospital Zuerich, Zuerich, Switzerland.|Division of Hepatology, Department of Medicine II, University Hospital Wuerzburg, Wuerzburg, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Geier
authors.affiliation: Institute of Pharmacology and Toxicology, University of Wuerzburg, Wuerzburg, Germany.
authors.forename: Helga
authors.initials: H
authors.lastname: Stopper
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D020552:Comet Assay; D004249:DNA Damage; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D008099:Liver / Q000378:metabolism / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018384:Oxidative Stress; D051059:PTEN Phosphohydrolase / Q000502:physiology*; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D017382:Reactive Oxygen Species; D051059:PTEN Phosphohydrolase