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PLoS One. 2016 Nov 15;11(11):e0166386. doi: 10.1371/journal.pone.0166386. eCollection 2016.

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

Chen X1,2,3, Tzekov R4,5, Su M3, Hong H3, Min W6, Han A3, Li W1.

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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.
Department of Ophthalmology, University of South Florida, Tampa, Florida, United States of America.
The Roskamp Institute, Sarasota, Florida, United States of America.
Interdepartmental Program in Vascular Biology and Therapeutics, Department of Pathology, Yale University School of Medicine, New Haven, Connecticut, United States of America.


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.

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