The polyether ionophore salinomycin targets multiple cellular pathways to block proliferative vitreoretinopathy pathology

English version

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
prolekare.web.journal.doi_sk: 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 – Biochemistry – Proteins – Developmental biology – Cellular types – Animal cells – Anatomy – Medicine and health sciences – Cell motility – Connective tissue cells – Fibroblasts – Biological tissue – Connective tissue – Collagens – Ophthalmology – Signal transduction – Cell signaling – Signaling cascades – Post-translational modification – TGF-beta signaling cascade – Phosphorylation – Retinal disorders – SMAD signaling – Signal inhibition – Cell migration – Retinal detachment

Zdroje

1. Tseng W, Cortez RT, Ramirez G, Stinnett S, Jaffe GJ. Prevalence and risk factors for proliferative vitreoretinopathy in eyes with rhegmatogenous retinal detachment but no previous vitreoretinal surgery. Am J Ophthalmol. 2004;137: 1105–1115. doi: 10.1016/j.ajo.2004.02.008 15183797

2. Cardillo JA, Stout JT, LaBree L, Azen SP, Omphroy L, Cui JZ, et al. Post-traumatic proliferative vitreoretinopathy. The epidemiologic profile, onset, risk factors, and visual outcome. Ophthalmology. 1997;104: 1166–1173. 9224471

3. Abrams GW, Azen SP, McCuen BW, Flynn HW, Lai MY, Ryan SJ. Vitrectomy with silicone oil or long-acting gas in eyes with severe proliferative vitreoretinopathy: results of additional and long-term follow-up. Silicone Study report 11. Arch Ophthalmol. 1997;115: 335–344. doi: 10.1001/archopht.1997.01100150337005 9076205

4. Grierson I, Hiscott PS, Hitchins CA, McKechnie NM, White VA, McLeod D. Which cells are involved in the formation of epiretinal membranes? Seminars in Ophthalmology. 1987;2: 99–109. doi: 10.3109/08820538709062514

5. Hiscott PS, Grierson I, McLeod D. Retinal pigment epithelial cells in epiretinal membranes: an immunohistochemical study. Br J Ophthalmol. 1984;68: 708–715. doi: 10.1136/bjo.68.10.708 6206888

6. Hiscott P, Sheridan C, Magee RM, Grierson I. Matrix and the retinal pigment epithelium in proliferative retinal disease. Prog Retin Eye Res. 1999;18: 167–190. 9932282

7. Li H, Wang H, Wang F, Gu Q, Xu X. Snail involves in the transforming growth factor β1-mediated epithelial-mesenchymal transition of retinal pigment epithelial cells. PLoS ONE. 2011;6: e23322. doi: 10.1371/journal.pone.0023322 21853110

8. Hinton DR, He S, Jin ML, Barron E, Ryan SJ. Novel growth factors involved in the pathogenesis of proliferative vitreoretinopathy. Eye (Lond). 2002;16: 422–428. doi: 10.1038/sj.eye.6700190 12101449

9. Lei H, Rheaume M-A, Kazlauskas A. Recent developments in our understanding of how platelet-derived growth factor (PDGF) and its receptors contribute to proliferative vitreoretinopathy. Exp Eye Res. 2010;90: 376–381. doi: 10.1016/j.exer.2009.11.003 19931527

10. Pennock S, Haddock LJ, Eliott D, Mukai S, Kazlauskas A. Is neutralizing vitreal growth factors a viable strategy to prevent proliferative vitreoretinopathy? Prog Retin Eye Res. 2014;40: 16–34. doi: 10.1016/j.preteyeres.2013.12.006 24412519

11. Chen Z, Shao Y, Li X. The roles of signaling pathways in epithelial-to-mesenchymal transition of PVR. Mol Vis. 2015;21: 706–710. 26109834

12. Anderson DH, Stern WH, Fisher SK, Erickson PA, Borgula GA. The onset of pigment epithelial proliferation after retinal detachment. Invest Ophthalmol Vis Sci. 1981;21: 10–16. 7251293

13. Kiilgaard JF, Prause JU, Prause M, Scherfig E, Nissen MH, la Cour M. Subretinal posterior pole injury induces selective proliferation of RPE cells in the periphery in in vivo studies in pigs. Invest Ophthalmol Vis Sci. 2007;48: 355–360. doi: 10.1167/iovs.05-1565 17197554

14. Massagué J. TGFβ signalling in context. Nat Rev Mol Cell Biol. 2012;13: 616–630. doi: 10.1038/nrm3434 22992590

15. Baudouin C, Fredj-Reygrobellet D, Brignole F, Nègre F, Lapalus P, Gastaud P. Growth factors in vitreous and subretinal fluid cells from patients with proliferative vitreoretinopathy. Ophthalmic Res. 1993;25: 52–59. doi: 10.1159/000267221 8446368

16. Pennock S, Rheaume M-A, Mukai S, Kazlauskas A. A novel strategy to develop therapeutic approaches to prevent proliferative vitreoretinopathy. Am J Pathol. 2011;179: 2931–2940. doi: 10.1016/j.ajpath.2011.08.043 22035642

17. Gamulescu M-A, Chen Y, He S, Spee C, Jin M, Ryan SJ, et al. Transforming growth factor beta2-induced myofibroblastic differentiation of human retinal pigment epithelial cells: regulation by extracellular matrix proteins and hepatocyte growth factor. Exp Eye Res. 2006;83: 212–222. doi: 10.1016/j.exer.2005.12.007 16563380

18. Raymond MC, Thompson JT. RPE-mediated collagen gel contraction. Inhibition by colchicine and stimulation by TGF-beta. Invest Ophthalmol Vis Sci. 1990;31: 1079–1086. 2354911

19. Choi K, Lee K, Ryu S-W, Im M, Kook KH, Choi C. Pirfenidone inhibits transforming growth factor-β1-induced fibrogenesis by blocking nuclear translocation of Smads in human retinal pigment epithelial cell line ARPE-19. Mol Vis. 2012;18: 1010–1020. 22550395

20. Woeller CF, O’Loughlin CW, Roztocil E, Feldon SE, Phipps RP. Salinomycin and other polyether ionophores are a new class of antiscarring agent. J Biol Chem. 2015;290: 3563–3575. doi: 10.1074/jbc.M114.601872 25538236

21. Bourlier V, Sengenès C, Zakaroff-Girard A, Decaunes P, Wdziekonski B, Galitzky J, et al. TGFbeta family members are key mediators in the induction of myofibroblast phenotype of human adipose tissue progenitor cells by macrophages. PLoS ONE. 2012;7: e31274. doi: 10.1371/journal.pone.0031274 22355352

22. George SJ. Regulation of myofibroblast differentiation by convergence of the Wnt and TGF-beta1/Smad signaling pathways. J Mol Cell Cardiol. 2009;46: 610–611. doi: 10.1016/j.yjmcc.2009.02.008 19233190

23. He H, Kuriyan AE, Su C-W, Mahabole M, Zhang Y, Zhu Y-T, et al. Inhibition of Proliferation and Epithelial Mesenchymal Transition in Retinal Pigment Epithelial Cells by Heavy Chain-Hyaluronan/Pentraxin 3. Sci Rep. 2017;7: 43736. doi: 10.1038/srep43736 28252047

24. Jonkman JEN, Cathcart JA, Xu F, Bartolini ME, Amon JE, Stevens KM, et al. An introduction to the wound healing assay using live-cell microscopy. Cell Adh Migr. 2014;8: 440–451. doi: 10.4161/cam.36224 25482647

25. Schiro JA, Chan BM, Roswit WT, Kassner PD, Pentland AP, Hemler ME, et al. Integrin alpha 2 beta 1 (VLA-2) mediates reorganization and contraction of collagen matrices by human cells. Cell. 1991;67: 403–410. doi: 10.1016/0092-8674(91)90191-z 1913826

26. Yang CH, Liu CZ, Huang TF, Yang CM, Lui KR, Chen MS, et al. Inhibition of RPE cell-mediated matrix adhesion and collagen gel contraction by crovidisin, a collagen-binding snake venom protein. Curr Eye Res. 1997;16: 1119–1126. doi: 10.1076/ceyr.16.11.1119.5106 9395771

27. Montesano R, Orci L. Transforming growth factor beta stimulates collagen-matrix contraction by fibroblasts: implications for wound healing. Proc Natl Acad Sci USA. 1988;85: 4894–4897. doi: 10.1073/pnas.85.13.4894 3164478

28. Dvashi Z, Goldberg M, Adir O, Shapira M, Pollack A. TGF-β1 induced transdifferentiation of rpe cells is mediated by TAK1. PLoS ONE. 2015;10: e0122229. doi: 10.1371/journal.pone.0122229 25849436

29. Ninomiya-Tsuji J, Kajino T, Ono K, Ohtomo T, Matsumoto M, Shiina M, et al. A resorcylic acid lactone, 5Z-7-oxozeaenol, prevents inflammation by inhibiting the catalytic activity of TAK1 MAPK kinase kinase. J Biol Chem. 2003;278: 18485–18490. doi: 10.1074/jbc.M207453200 12624112

30. Inman GJ, Nicolás FJ, Callahan JF, Harling JD, Gaster LM, Reith AD, et al. SB-431542 is a potent and specific inhibitor of transforming growth factor-beta superfamily type I activin receptor-like kinase (ALK) receptors ALK4, ALK5, and ALK7. Mol Pharmacol. 2002;62: 65–74. doi: 10.1124/mol.62.1.65 12065756

31. Jun EJ, Kim HS, Kim YH. Role of HGF/c-Met in serum-starved ARPE-19 cells. Korean J Ophthalmol. 2007;21: 244–250. doi: 10.3341/kjo.2007.21.4.244 18063891

32. Naujokat C, Fuchs D, Opelz G. Salinomycin in cancer: A new mission for an old agent. Mol Med Rep. 2010;3: 555–559. doi: 10.3892/mmr_00000296 21472278

33. Naujokat C, Steinhart R. Salinomycin as a drug for targeting human cancer stem cells. J Biomed Biotechnol. 2012;2012: 950658. doi: 10.1155/2012/950658 23251084

34. Zhou S, Wang F, Wong ET, Fonkem E, Hsieh T-C, Wu JM, et al. Salinomycin: a novel anti-cancer agent with known anti-coccidial activities. Curr Med Chem. 2013;20: 4095–4101. doi: 10.2174/15672050113109990199 23931281

35. Antoszczak M, Huczyński A. Anticancer Activity of Polyether Ionophore-Salinomycin. Anticancer Agents Med Chem. 2015;15: 575–591. 25553435

36. Zhang C, Lu Y, Li Q, Mao J, Hou Z, Yu X, et al. Salinomycin suppresses TGF-β1-induced epithelial-to-mesenchymal transition in MCF-7 human breast cancer cells. Chem Biol Interact. 2016;248: 74–81. doi: 10.1016/j.cbi.2016.02.004 26896736

37. Shih Y-H, Radeke MJ, Radeke CM, Coffey PJ. Restoration of Mesenchymal RPE by Transcription Factor-Mediated Reprogramming. Invest Ophthalmol Vis Sci. 2017;58: 430–441. doi: 10.1167/iovs.16-20018 28118667

38. Gu L, Zhu Y-J, Yang X, Guo Z-J, Xu W-B, Tian X-L. Effect of TGF-beta/Smad signaling pathway on lung myofibroblast differentiation. Acta Pharmacol Sin. 2007;28: 382–391. doi: 10.1111/j.1745-7254.2007.00468.x 17303001

39. Hu H-H, Chen D-Q, Wang Y-N, Feng Y-L, Cao G, Vaziri ND, et al. New insights into TGF-β/Smad signaling in tissue fibrosis. Chem Biol Interact. 2018;292: 76–83. doi: 10.1016/j.cbi.2018.07.008 30017632

The polyether ionophore salinomycin targets multiple cellular pathways to block proliferative vitreoretinopathy pathology

Souhrn

Klíčová slova:

Zdroje

PLOS One

Aktuální možnosti diagnostiky a léčby litiáz