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.
Highlights
Proliferative vitreoretinopathy (PVR) is caused by the growth and contraction of cellular membranes within the vitreous cavity and on retinal surfaces, and is a sight-threatening disease [1]
We found that AF inhibited cell survival in endothelial cell lines that were derived from axillary lymph node/vascular epithelium by down-regulating vascular endothelial growth factor receptor-3 and inducing P38 mitogen-activated protein kinase (P38MAPK) phosphorylation [18]
We found that the expression level of total c-Jun protein was up-regulated, whereas the expression levels of total MAPKAPK2 protein was slightly reduced after application of 2.0μM and 3.0μM AF, and expression levels of total heat shock protein 27 (HSP27) protein were slightly increased after application of 2.0 μM AF, but reduced after 3.0μM AF (Fig 4A and 4B)
Summary
Proliferative vitreoretinopathy (PVR) is caused by the growth and contraction of cellular membranes within the vitreous cavity and on retinal surfaces, and is a sight-threatening disease [1]. Retinal pigment epithelium (RPE) and glial cells were identified as main participants in the pathophysiology of PVR [2]. RPE cell proliferation and migration following retina detachment or trauma have been considered as a key element in the induction of PVR[1]. This process resembles fibrotic wound healing by the RPE cells. Many efforts have been reported in trying to solve the problem by inhibiting cell proliferation, successful and long-lasting treatment of PVR remains a challenge
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