LYTAK1 attenuates proliferation of retinal pigment epithelial cells through TGF‑β‑mediated epithelial‑mesenchymal transition via the ERK/AKT signaling pathway

Chen,Zhen; Ni,Ninghua; Mei,Yan; Yang,Zhengrong

doi:10.3892/etm.2017.5187

LYTAK1 attenuates proliferation of retinal pigment epithelial cells through TGF‑β‑mediated epithelial‑mesenchymal transition via the ERK/AKT signaling pathway

Authors:
- Zhen Chen
- Ninghua Ni
- Yan Mei
- Zhengrong Yang
View Affiliations

Affiliations: Department of Ophthalmology, The First People's Hospital of Yunnan, Kunming, Yunnan 650032, P.R. China, Research Center of Fundus Disease of Yunnan, The First People's Hospital of Yunnan, Kunming, Yunnan 650032, P.R. China
Published online on: September 22, 2017 https://doi.org/10.3892/etm.2017.5187
Pages: 4951-4957
Copyright: © Chen et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Retinal pigment epithelial (RPE) cells have crucial roles in the initiation and development of human ophthalmic diseases. Our previous study suggested that transforming growth factor‑β (TGF‑β)‑activated kinase 1 (TAK1) is a potential target in the progression and pathogenesis of human proliferative vitreoretinopathy disease. The present study further analyzed the role of TAK1 inhibitor, LYTAK1, in human RPE cells and explored the potential molecular mechanism of LYTAK1‑mediated proliferation of human RPE cells. Proliferation of human RPE cells was investigated following treatment with LYTAK1 and knockdown of TGF‑β. TGF‑β‑mediated epithelial‑mesenchymal transition (EMT) through regulation of the extracellular signal‑regulated kinase (ERK)/protein kinase B (AKT) signaling pathway was also explored to analyze the LYTAK1‑mediated mechanism of proliferation in human RPE cells. The present results demonstrated that LYTAK1 administration suppressed TAK1 gene and protein expression in human RPE cells. LYTAK1 administration also inhibited proliferation and migration of human RPE cells in vitro. Outcomes indicated that LYTAK1 treatment downregulated expression levels of TGF‑β1 and EMT markers, including cadherin, fibronectin and α‑smooth muscle actin in human RPE cells. Notably, results demonstrated that the ERK/AKT signal pathway was blocked by LYTAK1 in human RPE cells. Knockdown of TGF‑β markedly inhibited phosphorylation and activity of TAK1 and suppressed the LYTAK1‑mediated ERK/AKT signaling pathway in RPE cells, which further canceled inhibition of RPE cell proliferation by LYTAK1. In conclusion, these findings indicated that LYTAK1 may inhibit RPE cell proliferation through the TGF‑β‑mediated EMT/ERK/AKT signaling pathway, suggesting that TAK1 may be a potential target for the treatment of RPE diseases.

View Figures

View References

1	Devarajan G, Niven J, Forrester JV and Crane IJ: Retinal pigment epithelial cell apoptosis is influenced by a combination of macrophages and soluble mediators present in age-related macular degeneration. Curr Eye Res. 41:1235–1244. 2016. View Article : Google Scholar : PubMed/NCBI
2	Chen M, Rajapakse D, Fraczek M, Luo C, Forrester JV and Xu H: Retinal pigment epithelial cell multinucleation in the aging eye-a mechanism to repair damage and maintain homoeostasis. Aging Cell. 15:436–445. 2016. View Article : Google Scholar : PubMed/NCBI
3	Joshi R, Mankowski W, Winter M, Saini JS, Blenkinsop TA, Stern JH, Temple S and Cohen AR: Automated measurement of cobblestone morphology for characterizing stem cell derived retinal pigment epithelial cell cultures. J Ocul Pharmacol Ther. 32:331–339. 2016. View Article : Google Scholar : PubMed/NCBI
4	Hanus J, Anderson C, Sarraf D, Ma J and Wang S: Retinal pigment epithelial cell necroptosis in response to sodium iodate. Cell Death Discov. 2:160542016. View Article : Google Scholar : PubMed/NCBI
5	Lee GY, Kang SJ, Lee SJ, Song JE, Joo CK, Lee D and Khang G: Effects of small intestinal submucosa content on the adhesion and proliferation of retinal pigment epithelial cells on SIS-PLGA films. J Tissue Eng Regen Med. 11:99–108. 2017. View Article : Google Scholar : PubMed/NCBI
6	Brandstetter C, Patt J, Holz FG and Krohne TU: Inflammasome priming increases retinal pigment epithelial cell susceptibility to lipofuscin phototoxicity by changing the cell death mechanism from apoptosis to pyroptosis. J Photochem Photobiol B. 161:177–183. 2016. View Article : Google Scholar : PubMed/NCBI
7	Ying L, Chunxia Y and Wei L: Inhibition of ovarian cancer cell growth by a novel TAK1 inhibitor LYTAK1. Cancer Chemother Pharmacol. 76:641–650. 2015. View Article : Google Scholar : PubMed/NCBI
8	Sakurai H: Targeting of TAK1 in inflammatory disorders and cancer. Trends Pharmacol Sci. 33:522–530. 2012. View Article : Google Scholar : PubMed/NCBI
9	Zhou J, Zheng B, Ji J, Shen F, Min H, Liu B, Wu J and Zhang S: LYTAK1, a novel TAK1 inhibitor, suppresses KRAS mutant colorectal cancer cell growth in vitro and in vivo. Tumour Biol. 36:3301–3308. 2015. View Article : Google Scholar : PubMed/NCBI
10	Green YA, Ben-Yaakov K, Adir O, Pollack A and Dvashi Z: TAK1 is involved in the autophagy process in retinal pigment epithelial cells. Biochem Cell Biol. 94:188–196. 2016. View Article : Google Scholar : PubMed/NCBI
11	Dvashi Z, Green Y and Pollack A: TAK1 inhibition accelerates cellular senescence of retinal pigment epithelial cells. Invest Ophthalmol Vis Sci. 55:5679–5686. 2014. View Article : Google Scholar : PubMed/NCBI
12	Chen Z, Mei Y, Lei H, Tian R, Ni N, Han F, Gan S and Sun S: LYTAK1, a TAK1 inhibitor, suppresses proliferation and epithelialmesenchymal transition in retinal pigment epithelium cells. Mol Med Rep. 14:145–150. 2016. View Article : Google Scholar : PubMed/NCBI
13	Chou WW, Chen KC, Wang YS, Wang JY, Liang CL and Juo SH: The role of SIRT1/AKT/ERK pathway in ultraviolet B induced damage on human retinal pigment epithelial cells. Toxicol In Vitro. 27:1728–1736. 2013. View Article : Google Scholar : PubMed/NCBI
14	Jiang Q, Cao C, Lu S, Kivlin R, Wallin B, Chu W, Bi Z, Wang X and Wan Y: MEK/ERK pathway mediates UVB-induced AQP1 downregulation and water permeability impairment in human retinal pigment epithelial cells. Int J Mol Med. 23:771–777. 2009. View Article : Google Scholar : PubMed/NCBI
15	Lee EJ, Park SJ, Kang SK, Kim GH, Kang HJ, Lee SW, Jeon HB and Kim HS: Spherical bullet formation via E-cadherin promotes therapeutic potency of mesenchymal stem cells derived from human umbilical cord blood for myocardial infarction. Mol Ther. 20:1424–1433. 2012. View Article : Google Scholar : PubMed/NCBI
16	Chung EJ, Chun JN, Jung SA, Cho JW and Lee JH: TGF-β-stimulated aberrant expression of class III β-tubulin via the ERK signaling pathway in cultured retinal pigment epithelial cells. Biochem Biophys Res Commun. 415:367–372. 2011. View Article : Google Scholar : PubMed/NCBI
17	Zhao P, Torcaso A, Mariano A, Xu L, Mohsin S, Zhao L and Han R: Anoctamin 6 regulates C2C12 myoblast proliferation. PLoS One. 9:e927492014. View Article : Google Scholar : PubMed/NCBI
18	Chong CM and Zheng W: Artemisinin protects human retinal pigment epithelial cells from hydrogen peroxide-induced oxidative damage through activation of ERK/CREB signaling. Redox Biol. 9:50–56. 2016. View Article : Google Scholar : PubMed/NCBI
19	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(-Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
20	Stamp ME, Brugger MS, Wixforth A and Westerhausen C: Acoustotaxis -in vitro stimulation in a wound healing assay employing surface acoustic waves. Biomater Sci. 4:1092–1099. 2016. View Article : Google Scholar : PubMed/NCBI
21	Kwon OW, Song JH and Roh MI: Retinal Detachment and Proliferative Vitreoretinopathy. Dev Ophthalmol. 55:154–162. 2016. View Article : Google Scholar : PubMed/NCBI
22	Lai FH, Lo EC, Chan VC, Brelen M, Lo WL and Young AL: Combined pars plana vitrectomy-scleral buckle versus pars plana vitrectomy for proliferative vitreoretinopathy. Int Ophthalmol. 36:217–224. 2016. View Article : Google Scholar : PubMed/NCBI
23	García S, López E and López-Colomé AM: Glutamate accelerates RPE cell proliferation through ERK1/2 activation via distinct receptor-specific mechanisms. J Cell Biochem. 104:377–390. 2008. View Article : Google Scholar : PubMed/NCBI
24	Palma-Nicolás JP, López E and López-Colomé AM: Thrombin stimulates RPE cell motility by PKC-zeta- and NF-kappaB-dependent gene expression of MCP-1 and CINC-1/GRO chemokines. J Cell Biochem. 110:948–967. 2010. View Article : Google Scholar : PubMed/NCBI
25	Sheridan CM, Magee RM, Hiscott PS, Hagan S, Wong DH, McGalliard JN and Grierson I: The role of matricellular proteins thrombospondin-1 and osteonectin during RPE cell migration in proliferative vitreoretinopathy. Curr Eye Res. 25:279–285. 2002. View Article : Google Scholar : PubMed/NCBI
26	Winkler J and Hoerauf H: TGF-ß and RPE-derived cells in taut subretinal strands from patients with proliferative vitreoretinopathy. Eur J Ophthalmol. 21:422–426. 2011. View Article : Google Scholar : PubMed/NCBI
27	He S, Barron E, Ishikawa K, Khanamiri H Nazari, Spee C, Zhou P, Kase S, Wang Z, Dustin LD and Hinton DR: Inhibition of DNA methylation and methyl-CpG-binding protein 2 suppresses RPE transdifferentiation: Relevance to proliferative vitreoretinopathy. Invest Ophthalmol Vis Sci. 56:5579–5589. 2015. View Article : Google Scholar : PubMed/NCBI
28	Enzmann V, Hollborn M, Wiedemann P and Kohen L: Minor influence of the immunosuppressive cytokines IL-10 and TGF-beta on the proliferation and apoptosis of human retinal pigment epithelial (RPE) cells in vitro. Ocular Immunol Inflamm. 9:259–266. 2001. View Article : Google Scholar
29	Alge-Priglinger CS, André S, Schoeffl H, Kampik A, Strauss RW, Kernt M, Gabius HJ and Priglinger SG: Negative regulation of RPE cell attachment by carbohydrate-dependent cell surface binding of galectin-3 and inhibition of the ERK-MAPK pathway. Biochimie. 93:477–488. 2011. View Article : Google Scholar : PubMed/NCBI
30	Qin D, Zheng XX and Jiang YR: Apelin-13 induces proliferation, migration, and collagen I mRNA expression in human RPE cells via PI3K/Akt and MEK/Erk signaling pathways. Mol Vis. 19:2227–2236. 2013.PubMed/NCBI
31	Tang B, Cai J, Sun L, Li Y, Qu J, Snider BJ and Wu S: Proteasome inhibitors activate autophagy involving inhibition of PI3K-Akt-mTOR pathway as an anti-oxidation defense in human RPE cells. PLoS One. 9:e1033642014. View Article : Google Scholar : PubMed/NCBI
32	Bulloj A, Duan W and Finnemann SC: PI 3-kinase independent role for AKT in F-actin regulation during outer segment phagocytosis by RPE cells. Exp Eye Res. 113:9–18. 2013. View Article : Google Scholar : PubMed/NCBI
33	Cheung YH, Sheridan CM, Lo AC and Lai WW: Lectin from Agaricus bisporus inhibited S phase cell population and Akt phosphorylation in human RPE cells. Invest Ophthalmol Vis Sci. 53:7469–7475. 2012. View Article : Google Scholar : PubMed/NCBI