HSP90 as a novel therapeutic target for posterior capsule opacification. (December 2019)

• Record Type: Journal Article
• Authors: Li, Jing; Xue, Wenxian; Wang, Xuance; Huang, Weikang; Wang, Xiang-Xiang; Li, Hui; Cui, Xiukun; Li, Mengyuan; Mu, Hongmei; Ren, Yanzhu; Zhang, Fengyan; Hu, Yanzhong
• Is Part Of: Experimental eye research. Volume 189(2019)
• Publication Date: 2019-12
• Subjects: HSP90 -- Posterior capsular opacification -- 17-AAG -- EGFR -- Cataract; EGF (Epithelial growth factor) -- EGFR (EGF receptor) -- TGF-β2 (transforming growth factor-β2) -- TGFR (TGF-β2 receptor) -- EMT (Epithelial-Mesenchymal transition) -- ERK (extracellular regulated protein kinase) -- MAPK (Mitogen-activated protein kinase) -- mTOR (mammalian target of rapamycin) -- SMAD (drosophila mothers against decapentaplegic protein) -- α-SMA (smooth muscle actin) -- HSP (heat shock protein) -- HSF1 (heat shock factor 1) -- 17-AAG (Tanespimycin) -- IPI504 (Retaspimycin hydrochloride) -- MTT (3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide); Ophthalmology -- Periodicals; Eye -- Periodicals; Œil -- Périodiques; Ophthalmology; Periodicals; Electronic journals; 612.8405
• DOI: 10.1016/j.exer.2019.107821
• Languages: English
• ISSNs: 0014-4835

Abstract

Abstract: Posterior capsule opacification (PCO) is a common complication of cataract surgery, resulting from a combination of proliferation, migration, epithelial-mesenchymal transition (EMT) of residual capsular epithelial cells and fibrosis of myofibroblasts. HSP90 is known to regulate the proteostasis of cells under pathophysiological conditions. The role of HSP90 in PCO formation, however, is not clear. To do this, the lens epithelial cell lines and an ex vivo cultured rat capsular bag model were used to study the role of HSP90 in PCO formation. The expression of protein and mRNA was measured by immunoblotting and quantitative RT-PCR, and cell apoptosis was measured by TUNEL(TdT-mediated dUTP nick-end labeling). The cell proliferation was measured by cell viability assays. The results showed that 17-AAG (Tanespimycin), an inhibitor of HSP90, suppresses the proliferation of immortalized lens epithelial cell lines HLE-B3, SRA01/04, and mLEC, with IC50 values of 0.27, 0.27, and 0.49 μM, respectively. In an ex vivo cultured rat capsular model, the capsular residual epithelial cells resisted the stress of the capsulorhexis surgery and took 3–6 days to completely overlay the capsular posterior wall. During this process, heat shock factor 1 and its downstream targets HSP90, HSP25, αB-crystallin, and HSP40 were upregulated. Treatment with 17-AAG inhibited the viability of capsular residual epithelial cells and induced the cells apoptosis, characterized by increases in ROS levels, apoptotic DNA injury, and the activation of caspases 9 and 3. HSP90 participated in regulating both EGF receptor (EGFR) and TGF receptor (TGFR) signaling pathways. HSP90 was found to interact with the EGFR, such that inhibition of HSP90 by 17-AAG destabilized the EGFR protein and suppressed p-ERK1/2 and p-AKT levels. 17-AAG also inhibited the TGF-β-induced phosphorylation of SMAD2/3 and ERK1/2 and the decrease in E-cadherin and ZO-1 expression. Accordingly, these data suggest that the induction of HSP90 protects capsular residual epithelial cells against capsulorhexis-induced stress and participates in regulating the processes of proliferation, EMT and migration of rat capsular residual epithelial cells, at least partly, through the EGFR and TGFR signaling pathways. Treatment with 17-AAG suppresses PCO formation and is therefore a potential therapeutic candidate for PCO prevention. Highlights: HSP90 is induced in ex vivo cultured rat capsular residual cells. 17-AAG exhibits the cytotoxicity to rat capsular residual cells but not to corneal cells. HSP90 interacts with EGFR signaling pathway regulating capsular residual cell proliferation. 17-AAG is a novel potential therapeutic drug for PCO.