title: Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway.
abstract: Abnormal survival of retinal pigment epithelium (RPE) cells contributes to the pathogenesis of proliferative vitreoretinopathy (PVR), a sight-threatening disease. In this study, we explored the effect of the anti-rheumatic agent auranofin (AF) on RPE cell survival and studied the underlying signaling mechanisms in vitro. Our results showed that AF inhibited ARPE-19 cell survival in a dose and time-dependent manner. Application of AF induced several effects: a significant decrease in total epidermal growth factor receptor (EGFR) and an increase in phosphorylated EGFR and mitogen-activated protein kinase (MAPK), including extracellular signal-regulated kinase (ERK), P38 mitogen-activated protein kinase (P38MAPK), c-Jun N-terminal kinase (JNK), c-Jun, mitogen activated protein kinase activated protein kinase 2(MAPKAPK2), and heat shock protein 27 (HSP27). AF also inhibited epidermal growth factor (EGF)-dependent cell proliferation and migration through affecting EGFR/MAPK signaling. The antioxidant N-acetylcysteine (NAC) blocked the AF-induced increase of reactive oxygen species (ROS) production, the reduction of total EGFR, and the phosphorylation of multiple nodes in EGFR/MAPK signaling pathway. P38MAPK inhibitor SB203580, but not inhibitors of EGFR (erlotinib), ERK (FR180204) and JNK (SP600125), suppressed AF-induced phosphorylation of EGFR/p38MAPK/MAPKAPK2/Hsp27. In conclusion, the ROS-dependent phosphorylation of EGFR/MAPK is an important signaling pathway for AF-induced inhibition of RPE cell survival, and AF may have the potential for treatment of abnormal survival of RPE cells in PVR.
authors.affiliation: Xiamen Eye Center of Xiamen University, Xiamen University, Xiamen, Fujian, China.|Department of Ophthalmology, First Hospital of Xi'an, Shanxi Institute of Ophthalmology, Shanxi Provincial Key Laboratory of Ophthalmology, Xi'an, Shanxi, China.|State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiangan, Xiamen, China.
authors.forename: Xiaodong
authors.initials: X
authors.lastname: Chen
authors.affiliation: Department of Ophthalmology, University of South Florida, Tampa, Florida, United States of America.|The Roskamp Institute, Sarasota, Florida, United States of America.
authors.forename: Radouil
authors.initials: R
authors.lastname: Tzekov
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiangan, Xiamen, China.
authors.forename: Mingyang
authors.initials: M
authors.lastname: Su
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiangan, Xiamen, China.
authors.forename: Haiyan
authors.initials: H
authors.lastname: Hong
authors.affiliation: Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America.
authors.forename: Wang
authors.initials: W
authors.lastname: Min
authors.affiliation: State Key Laboratory for Cellular Stress Biology, School of Life Sciences, Xiamen University, Xiangan, Xiamen, China.
authors.forename: Aidong
authors.initials: A
authors.lastname: Han
authors.affiliation: Xiamen Eye Center of Xiamen University, Xiamen University, Xiamen, Fujian, China.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Li
mesh_terms: D001310:Auranofin / Q000008:administration & dosage*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival; D066246:ErbB Receptors / Q000235:genetics*; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects; D010766:Phosphorylation; D017382:Reactive Oxygen Species / Q000378:metabolism; D055213:Retinal Pigment Epithelium / Q000187:drug effects*; D018630:Vitreoretinopathy, Proliferative / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D048051:p38 Mitogen-Activated Protein Kinases / Q000235:genetics*
chemical_list: D017382:Reactive Oxygen Species; D001310:Auranofin; C512478:EGFR protein, human; D066246:ErbB Receptors; D048051:p38 Mitogen-Activated Protein Kinases