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Current Molecular Medicine

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ISSN (Print): 1566-5240
ISSN (Online): 1875-5666

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Research Article

Toosendanin Restrains Idiopathic Pulmonary Fibrosis by Inhibiting ZEB1/CTBP1 Interaction

Author(s): Xingbin Li, Zina Bai, Zhensheng Li, Jun Wang and Xixin Yan*

Volume 24, Issue 1, 2024

Published on: 05 June, 2023

Page: [123 - 133] Pages: 11

DOI: 10.2174/1566524023666230501205149

Price: $65

Abstract

Background: Extensive deposition of extracellular matrix (ECM) in idiopathic pulmonary fibrosis (IPF) is due to hyperactivation and proliferation of pulmonary fibroblasts. However, the exact mechanism is not clear. Objective: This study focused on the role of CTBP1 in lung fibroblast function, elaborated its regulation mechanism, and analyzed the relationship between CTBP1 and ZEB1. Meanwhile, the antipulmonary fibrosis effect and its molecular mechanism of Toosendanin were studied.

Methods: Human IPF fibroblast cell lines (LL-97A and LL-29) and normal fibroblast cell lines (LL-24) were cultured in vitro. The cells were stimulated with FCS, PDGF-BB, IGF-1, and TGF-β1, respectively. BrdU detected cell proliferation. The mRNA expression of CTBP1 and ZEB1 was detected by QRT-PCR. Western blotting was used to detect the expression of COL1A1, COL3A1, LN, FN, and α-SMA proteins. An animal model of pulmonary fibrosis was established to analyze the effects of CTBP1 silencing on pulmonary fibrosis and lung function in mice.

Results: CTBP1 was up-regulated in IPF lung fibroblasts. Silencing CTBP1 inhibits growth factor-driven proliferation and activation of lung fibroblasts. Overexpression of CTBP1 promotes growth factor-driven proliferation and activation of lung fibroblasts. Silencing CTBP1 reduced the degree of pulmonary fibrosis in mice with pulmonary fibrosis. Western blot, CO-IP, and BrdU assays confirmed that CTBP1 interacts with ZEB1 and promotes the activation of lung fibroblasts. Toosendanin can inhibit the ZEB1/CTBP1protein interaction and further inhibit the progression of pulmonary fibrosis.

Conclusion: CTBP1 can promote the activation and proliferation of lung fibroblasts through ZEB1. CTBP1 promotes lung fibroblast activation through ZEB1, thereby increasing excessive deposition of ECM and aggravating IPF. Toosendanin may be a potential treatment for pulmonary fibrosis. The results of this study provide a new basis for clarifying the molecular mechanism of pulmonary fibrosis and developing new therapeutic targets.

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[1]
Lederer DJ, Martinez FJ. Idiopathic pulmonary fibrosis. N Engl J Med 2018; 378(19): 1811-23.
[http://dx.doi.org/10.1056/NEJMra1705751] [PMID: 29742380]
[2]
Reyfman PA, Walter JM, Joshi N, et al. Single-cell transcriptomic analysis of human lung provides insights into the pathobiology of pulmonary fibrosis. Am J Respir Crit Care Med 2019; 199(12): 1517-36.
[http://dx.doi.org/10.1164/rccm.201712-2410OC] [PMID: 30554520]
[3]
Maher TM, Strek ME. Antifibrotic therapy for idiopathic pulmonary fibrosis: Time to treat. Respir Res 2019; 20(1): 205.
[http://dx.doi.org/10.1186/s12931-019-1161-4] [PMID: 31492155]
[4]
Justice JN, Nambiar AM, Tchkonia T, et al. Senolytics in idiopathic pulmonary fibrosis: Results from a first-in-human, open-label, pilot study. Exp Biol Med 2019; 40: 554-63.
[http://dx.doi.org/10.1016/j.ebiom.2018.12.052] [PMID: 30616998]
[5]
Waters DW, Blokland KEC, Pathinayake PS, et al. Fibroblast senescence in the pathology of idiopathic pulmonary fibrosis. Am J Physiol Lung Cell Mol Physiol 2018; 315(2): L162-72.
[http://dx.doi.org/10.1152/ajplung.00037.2018] [PMID: 29696986]
[6]
Selman M, Pardo A. The leading role of epithelial cells in the pathogenesis of idiopathic pulmonary fibrosis. Cell Signal 2020; 66: 109482.
[http://dx.doi.org/10.1016/j.cellsig.2019.109482] [PMID: 31760172]
[7]
Jin J, Togo S, Kadoya K, et al. Pirfenidone attenuates lung fibrotic fibroblast responses to transforming growth factor-β1. Respir Res 2019; 20(1): 119.
[http://dx.doi.org/10.1186/s12931-019-1093-z] [PMID: 31185973]
[8]
Shi Y, Sawada J, Sui G, et al. Coordinated histone modifications mediated by a CtBP co-repressor complex. Nature 2003; 422(6933): 735-8.
[http://dx.doi.org/10.1038/nature01550] [PMID: 12700765]
[9]
Di LJ, Byun JS, Wong MM, et al. Genome-wide profiles of CtBP link metabolism with genome stability and epithelial reprogramming in breast cancer. Nat Commun 2013; 4(1): 1449.
[http://dx.doi.org/10.1038/ncomms2438] [PMID: 23385593]
[10]
Birts CN, Harding R, Soosaipillai G, et al. Expression of CtBP family protein isoforms in breast cancer and their role in chemoresistance. Biol Cell 2011; 103(1): 1-19.
[http://dx.doi.org/10.1042/BC20100067] [PMID: 20964627]
[11]
Zhao Z, Hao D, Wang L, et al. CtBP promotes metastasis of breast cancer through repressing cholesterol and activating TGF-β signaling. Oncogene 2019; 38(12): 2076-91.
[http://dx.doi.org/10.1038/s41388-018-0570-z] [PMID: 30442980]
[12]
Ding B, Yuan F, Damle PK, Litovchick L, Drapkin R, Grossman SR. CtBP determines ovarian cancer cell fate through repression of death receptors. Cell Death Dis 2020; 11(4): 286.
[http://dx.doi.org/10.1038/s41419-020-2455-7] [PMID: 32332713]
[13]
Weisiger RA, Fridovich I. Mitochondrial superoxide simutase. Site of synthesis and intramitochondrial localization. J Biol Chem 1973; 248(13): 4793-6.
[http://dx.doi.org/10.1016/S0021-9258(19)43735-6] [PMID: 4578091]
[14]
Mao H, Seo SJ, Biswal MR, et al. Mitochondrial oxidative stress in the retinal pigment epithelium leads to localized retinal degeneration. Invest Ophthalmol Vis Sci 2014; 55(7): 4613-27.
[http://dx.doi.org/10.1167/iovs.14-14633] [PMID: 24985474]
[15]
White NH, Sun W, Cleary PA, et al. Prolonged effect of intensive therapy on the risk of retinopathy complications in patients with type 1 diabetes mellitus: 10 years after the Diabetes Control and Complications Trial. Arch Ophthalmol 2008; 126(12): 1707-15.
[http://dx.doi.org/10.1001/archopht.126.12.1707] [PMID: 19064853]
[16]
Alpatov R, Munguba GC, Caton P, et al. Nuclear speckle-associated protein Pnn/DRS binds to the transcriptional corepressor CtBP and relieves CtBP-mediated repression of the E-cadherin gene. Mol Cell Biol 2004; 24(23): 10223-35.
[http://dx.doi.org/10.1128/MCB.24.23.10223-10235.2004] [PMID: 15542832]
[17]
Peña C, García JM, García V, et al. The expression levels of the transcriptional regulators p300 and CtBP modulate the correlations between SNAIL, ZEB1, E-cadherin and vitamin D receptor in human colon carcinomas. Int J Cancer 2006; 119(9): 2098-104.
[http://dx.doi.org/10.1002/ijc.22083] [PMID: 16804902]
[18]
Wellner U, Schubert J, Burk UC, et al. The EMT-activator ZEB1 promotes tumorigenicity by repressing stemness-inhibiting microRNAs. Nat Cell Biol 2009; 11(12): 1487-95.
[http://dx.doi.org/10.1038/ncb1998] [PMID: 19935649]
[19]
Postigo AA. Opposing functions of ZEB proteins in the regulation of the TGFbeta/BMP signaling pathway. EMBO J 2003; 22(10): 2443-52.
[http://dx.doi.org/10.1093/emboj/cdg225] [PMID: 12743038]
[20]
Sánchez-Tilló E, Lázaro A, Torrent R, et al. ZEB1 represses E-cadherin and induces an EMT by recruiting the SWI/SNF chromatin-remodeling protein BRG1. Oncogene 2010; 29(24): 3490-500.
[http://dx.doi.org/10.1038/onc.2010.102] [PMID: 20418909]
[21]
Shi YL, Li MF. Biological effects of toosendanin, a triterpenoid extracted from Chinese traditional medicine. Prog Neurobiol 2007; 82(1): 1-10.
[http://dx.doi.org/10.1016/j.pneurobio.2007.02.002] [PMID: 17363132]
[22]
Zhang S, Cao L, Wang ZR, Li Z, Ma J. Anti-cancer effect of toosendanin and its underlying mechanisms. J Asian Nat Prod Res 2019; 21(3): 270-83.
[http://dx.doi.org/10.1080/10286020.2018.1451516] [PMID: 29629572]
[23]
Zhang T, Li J, Yin F, et al. Toosendanin demonstrates promising antitumor efficacy in osteosarcoma by targeting STAT3. Oncogene 2017; 36(47): 6627-39.
[http://dx.doi.org/10.1038/onc.2017.270] [PMID: 28783167]
[24]
Zhang Y, Lu P, Qin H, et al. Traditional Chinese medicine combined with pulmonary drug delivery system and idiopathic pulmonary fibrosis: Rationale and therapeutic potential. Biomed Pharmacother 2021; 133: 111072.
[http://dx.doi.org/10.1016/j.biopha.2020.111072] [PMID: 33378971]
[25]
Moeller A, Ask K, Warburton D, Gauldie J, Kolb M. The bleomycin animal model: A useful tool to investigate treatment options for idiopathic pulmonary fibrosis? Int J Biochem Cell Biol 2008; 40(3): 362-82.
[http://dx.doi.org/10.1016/j.biocel.2007.08.011] [PMID: 17936056]
[26]
Peyser R, MacDonnell S, Gao Y, et al. Defining the activated fibroblast population in lung fibrosis using single-cell sequencing. Am J Respir Cell Mol Biol 2019; 61(1): 74-85.
[http://dx.doi.org/10.1165/rcmb.2018-0313OC] [PMID: 30848683]
[27]
Lee TH, Yeh CF, Lee YT, et al. Fibroblast-enriched endoplasmic reticulum protein TXNDC5 promotes pulmonary fibrosis by augmenting TGFβ signaling through TGFBR1 stabilization. Nat Commun 2020; 11(1): 4254.
[http://dx.doi.org/10.1038/s41467-020-18047-x] [PMID: 31911652]
[28]
Upagupta C, Shimbori C, Alsilmi R, Kolb M. Matrix abnormalities in pulmonary fibrosis. Eur Respir Rev 2018; 27(148): 180033.
[http://dx.doi.org/10.1183/16000617.0033-2018] [PMID: 29950306]
[29]
Saito A, Horie M, Micke P, Nagase T. The role of TGF-β signaling in lung cancer associated with idiopathic pulmonary fibrosis. Int J Mol Sci 2018; 19(11): 3611.
[http://dx.doi.org/10.3390/ijms19113611] [PMID: 30445777]
[30]
Inui N, Sakai S, Kitagawa M. Molecular Pathogenesis of pulmonary fibrosis, with focus on pathways related to TGF-β and the ubiquitin-proteasome pathway. Int J Mol Sci 2021; 22(11): 6107.
[http://dx.doi.org/10.3390/ijms22116107] [PMID: 34198949]
[31]
Willis BC, duBois RM, Borok Z. Epithelial origin of myofibroblasts during fibrosis in the lung. Proc Am Thorac Soc 2006; 3(4): 377-82.
[http://dx.doi.org/10.1513/pats.200601-004TK] [PMID: 16738204]
[32]
Hill C, Jones M G, Davies D E, Wang Y. Epithelialmesenchymal transition contributes to pulmonary fibrosis via aberrant epithelial/fibroblastic cross-talk. Journal of lung health and diseases 2019; 3(2): 31.
[33]
Cao B, Guo Z, Zhu Y, Xu W. The potential role of PDGF, IGF-1, TGF-β expression in idiopathic pulmonary fibrosis. Chin Med J (Engl) 2000; 113(9): 776-82.
[PMID: 11776068]
[34]
Daian T, Ishihara H, Hirano A, et al. Insulin-like growth factor-I enhances transforming growth factor-β-induced extracellular matrix protein production through the P38/activating transcription factor-2 signaling pathway in keloid fibroblasts. J Invest Dermatol 2003; 120(6): 956-62.
[http://dx.doi.org/10.1046/j.1523-1747.2003.12143.x] [PMID: 12787120]
[35]
Craig VJ, Zhang L, Hagood JS, Owen CA. Matrix metalloproteinases as therapeutic targets for idiopathic pulmonary fibrosis. Am J Respir Cell Mol Biol 2015; 53(5): 585-600.
[http://dx.doi.org/10.1165/rcmb.2015-0020TR] [PMID: 26121236]
[36]
Kuppuswamy M, Vijayalingam S, Zhao LJ, et al. Role of the PLDLS-binding cleft region of CtBP1 in recruitment of core and auxiliary components of the corepressor complex. Mol Cell Biol 2008; 28(1): 269-81.
[http://dx.doi.org/10.1128/MCB.01077-07] [PMID: 17967884]
[37]
Blevins MA, Huang M, Zhao R. The role of CtBP1 in oncogenic processes and its potential as a therapeutic target. Mol Cancer Ther 2017; 16(6): 981-90.
[http://dx.doi.org/10.1158/1535-7163.MCT-16-0592] [PMID: 28576945]
[38]
Singh M, Yelle N, Venugopal C, Singh SK. EMT: Mechanisms and therapeutic implications. Pharmacol Ther 2018; 182: 80-94.
[http://dx.doi.org/10.1016/j.pharmthera.2017.08.009] [PMID: 28834698]
[39]
Schmalhofer O, Brabletz S, Brabletz T. E-cadherin, β-catenin, and ZEB1 in malignant progression of cancer. Cancer Metastasis Rev 2009; 28(1-2): 151-66.
[http://dx.doi.org/10.1007/s10555-008-9179-y] [PMID: 19153669]
[40]
Cheng L, Zhou MY, Gu YJ, Chen L, Wang Y. ZEB1: New advances in fibrosis and cancer. Mol Cell Biochem 2021; 476(4): 1643-50.
[http://dx.doi.org/10.1007/s11010-020-04036-7] [PMID: 33417164]
[41]
Zhao X, Yang Y, Yu H, et al. Polydatin inhibits ZEB1‐invoked epithelial‐mesenchymal transition in fructose‐induced liver fibrosis. J Cell Mol Med 2020; 24(22): 13208-22.
[http://dx.doi.org/10.1111/jcmm.15933] [PMID: 33058500]
[42]
Yao L, Conforti F, Hill C, et al. Paracrine signalling during ZEB1-mediated epithelial–mesenchymal transition augments local myofibroblast differentiation in lung fibrosis. Cell Death Differ 2019; 26(5): 943-57.
[http://dx.doi.org/10.1038/s41418-018-0175-7] [PMID: 30050057]
[43]
Yu MX, Song X, Ma XQ, Hao CX, Huang JJ, Yang WH. Investigation into molecular mechanisms and high-frequency core TCM for pulmonary fibrosis secondary to COVID-19 based on network pharmacology and data mining. Ann Palliat Med 2021; 10(4): 3960-75.
[http://dx.doi.org/10.21037/apm-20-1384] [PMID: 33832291]
[44]
Lu ZH, Yang CL, Yang GG, et al. Efficacy of the combination of modern medicine and traditional Chinese medicine in pulmonary fibrosis arising as a sequelae in convalescent COVID-19 patients: A randomized multicenter trial. Infect Dis Poverty 2021; 10(1): 31.
[http://dx.doi.org/10.1186/s40249-021-00813-8] [PMID: 33731163]
[45]
Gu X, Wei W, Liu Z, et al. Assessment of traditional Chinese medicine pattern in a bleomycin-induced pulmonary fibrosis mouse model: A pilot study. J Trad Chinese Med Sci 2022; 9(4): 400-8.
[http://dx.doi.org/10.1016/j.jtcms.2022.09.005]
[46]
Li H, Zhao C, Muhetaer G, et al. Integrated RNA-sequencing and network pharmacology approach reveals the protection of Yiqi Huoxue formula against idiopathic pulmonary fibrosis by interfering with core transcription factors. Phytomedicine 2022; 104: 154301.
[http://dx.doi.org/10.1016/j.phymed.2022.154301] [PMID: 35792448]

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