The polyether ionophore salinomycin targets multiple cellular pathways to block proliferative vitreoretinopathy pathology
Autoři:
Alison M. Heffer aff001; Jacob Proaño aff001; Elisa Roztocil aff001; Richard P. Phipps aff002; Steven E. Feldon aff001; Krystel R. Huxlin aff001; Patricia J. Sime aff004; Richard T. Libby aff001; Collynn F. Woeller aff001; Ajay E. Kuriyan aff001
Působiště autorů:
Flaum Eye Institute, University of Rochester, Rochester, NY, United States of America
aff001; Department of Environmental Medicine, University of Rochester, Rochester, NY, United States of America
aff002; Center for Visual Sciences, University of Rochester, Rochester, NY, United States of America
aff003; Department of Medicine, University of Rochester, Rochester, NY, United States of America
aff004
Vyšlo v časopise:
PLoS ONE 14(9)
Kategorie:
Research Article
doi:
https://doi.org/10.1371/journal.pone.0222596
Souhrn
Proliferative vitreoretinopathy (PVR) is characterized by membranes that form in the vitreous cavity and on both surfaces of the retina, which results in the formation of tractional membranes that can cause retinal detachment and intrinsic fibrosis of the retina, leading to retina foreshortening. Currently, there are no pharmacologic therapies that are effective in inhibiting or preventing PVR formation. One of the key aspects of PVR pathogenesis is retinal pigment epithelial (RPE) cell epithelial mesenchymal transition (EMT). Here we show that the polyether ionophore compound salinomycin (SNC) effectively inhibits TGFβ-induced EMT of RPE cells. SNC blocks the activation of TGFβ-induced downstream targets alpha smooth muscle actin (αSMA) and collagen 1 (Col1A1). Additionally, SNC inhibits TGFβ-induced RPE cell migration and contraction. We show that SNC functions to inhibit RPE EMT by targeting both the pTAK1/p38 and Smad2 signaling pathways upon TGFβ stimulation. Additionally, SNC is able to inhibit αSMA and Col1A1 expression in RPE cells that have already undergone TGFβ-induced EMT. Together, these results suggest that SNC could be an effective therapeutic compound in both the prevention and treatment of PVR.
Klíčová slova:
Biology and life sciences – Cell biology – Signal transduction – Cell signaling – SMAD signaling – Signaling cascades – TGF-beta signaling cascade – Signal inhibition – Cell motility – Cell migration – Cellular types – Animal cells – Connective tissue cells – Fibroblasts – Biochemistry – Proteins – Collagens – Post-translational modification – Phosphorylation – Developmental biology – Anatomy – Biological tissue – Connective tissue – Medicine and health sciences – Ophthalmology – Retinal disorders – Retinal detachment
Zdroje
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Článek vyšel v časopise
PLOS One
2019 Číslo 9
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