Auranofin Inhibits Retinal Pigment Epithelium Cell Survival through Reactive Oxygen Species-Dependent Epidermal Growth Factor Receptor/ Mitogen-Activated Protein Kinase Signaling Pathway

• Published in: PloS one Vol. 11; no. 11; p. e0166386
• Main Authors: Chen, Xiaodong, Tzekov, Radouil, Su, Mingyang, Hong, Haiyan, Min, Wang, Han, Aidong, Li, Wensheng
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 15.11.2016; Public Library of Science (PLoS)
• Subjects: Acetylcysteine; Antioxidants; Antirheumatic agents; Apoptosis; Auranofin - administration & dosage; Biology; Biology and life sciences; c-Jun protein; Cancer; Cell cycle; Cell growth; Cell Line; Cell migration; Cell proliferation; Cell Proliferation - drug effects; Cell Survival; Cytokines; Epidermal growth factor; Epidermal growth factor receptors; Epidermal growth factors; Epithelium; ErbB Receptors - genetics; Extracellular signal-regulated kinase; Heat shock; Heat shock proteins; Hsp27 protein; Humans; Immunoglobulins; Inhibition; JNK protein; Kinases; Laboratories; Life sciences; MAP kinase; MAP Kinase Signaling System - drug effects; Mitogens; Oxidative stress; Oxygen; p38 Mitogen-Activated Protein Kinases - genetics; Pathogenesis; Phosphorylation; Protein kinase; Protein kinases; Proteins; Reactive oxygen species; Reactive Oxygen Species - metabolism; Retina; Retinal pigment epithelium; Retinal Pigment Epithelium - drug effects; Rheumatoid arthritis; Signal transduction; Signaling; Survival; Transcription factors; Vitreoretinopathy, Proliferative - drug therapy; Vitreoretinopathy, Proliferative - genetics; Vitreoretinopathy, Proliferative - pathology; Florida; United States > US; China
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0166386

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.