Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3β/β-catenin axis activation

Yan, Pengpeng; Tang, Huanna; Chen, Xiaoying; Ji, Shuiyu; Wei, Jin; Zhang, Jiaming; Shen, Jia; Deng, Hao; Zhao, Xiaojun; Shen, Quanquan; Huang, Hongfeng

doi:10.1042/bsr20180240

Cited by 10 publications

(9 citation statements)

References 38 publications

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“…They found that inhibiting β-catenin reversed the expression of high-glucose-induced EMT markers. In another study, high-glucose dialysate was reported to induce phosphorylation of glycogen synthase kinase (GSK)-3β and thus inhibit degradation of β-catenin [26]. Ultimately, this β-catenin signaling was implicated in EMT.…”

Section: Discussionmentioning

confidence: 99%

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Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

Kang

Kim

et al. 2019

Kidney Res Clin Pract

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BackgroundWe investigated the effects of tranilast on epithelial-to-mesenchymal transition (EMT) in an animal model and on the EMT signaling pathway in human peritoneal mesothelial cells (HPMCs).MethodsWe performed in vitro studies (cytotoxicity, cell morphology, and western blot analyses) on HPMCs from human omenta, along with in vivo studies (peritoneal membrane function and morphometric and immunohistochemical analyses) on Sprague Dawley rats. Thirty-two rats were divided into three groups: control (C) group (peritoneal dialysis [PD] catheter but not infused with dialysate), PD group (4.25% glucose-containing dialysate), and PD + tranilast group (4.25% glucose-containing dialysate along with tranilast).ResultsIn in vitro experiments, transforming growth factor-beta 1 (TGF-β1) increased α-smooth muscle actin and Snail expression and reduced E-cadherin expression in HPMCs. TGF-β1 also reduced cell contact, induced a fibroblastoid morphology, and increased phosphorylation of Akt, Smad2, and Smad3 in HPMCs. Tranilast significantly inhibited TGF-β1-induced EMT and attenuated these morphological changes in HPMCs. In in vivo studies, after 6 weeks of experimental PD, the peritoneal membrane was significantly thicker in the PD group than in the C group. Tranilast protected against PD-induced glucose mass transfer change and histopathological changes in rats.ConclusionTranilast prevented EMT both in HPMCs triggered with TGF-β1 and in rats with PD-induced peritoneal fibrosis. Thus, tranilast may be considered a therapeutic intervention that enables long-term PD by regulating TGF-β1 signaling pathways.

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Section: Discussionmentioning

confidence: 99%

“…Ultimately, this β-catenin signaling was implicated in EMT. Yan et al [26] investigated the association between high-glucose dialysate treatment and GSK-3β phosphorylation and demonstrated that tamoxifen downregulated the GSK-3β/β-catenin axis. Kazama et al [27] focused on the function of mast cells in progression of peritoneal fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

Kang

Kim

et al. 2019

Kidney Res Clin Pract

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“…Non-ATP competitive GSK 3β inhibitors, including LiCl, TDZD-8 and L803-mts, could also induce significant inhibition of tumor growth ( 108 ). A previous study has revealed that TWS119 could reverse the effects of tamoxifen on β-catenin and Snail expression thereby inhibiting GSK-3β/β-catenin activation ( 109 ). Furthermore, TWS119 exhibited different effects on CD4 + and CD8 + T cells in tumor-infiltrating lymphocytes (TILs) by stimulating the expansion of naive T cell and CD8 stem cell-like memory T cells, and inducing CD8 + effector T-cell proliferation in TILs ( 110 ).…”

Section: Gsk 3β Inhibitors In Antineoplastic Treatmentmentioning

confidence: 99%

Glycogen synthase kinase 3β in tumorigenesis and oncotherapy (Review)

Lei³

et al. 2020

Oncol Rep

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Glycogen synthase kinase 3β (GSK 3β), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. Therefore, aberrant regulation of GSK 3β results in a broad range of human diseases, such as tumors, diabetes, inflammation and neurodegenerative diseases. Accumulating evidence has suggested that GSK 3β is correlated with tumorigenesis and progression. However, GSK 3β is controversial due to its bifacial roles of tumor suppression and activation. In addition, overexpression of GSK 3β is involved in tumor growth, whereas it contributes to the cell sensitivity to chemotherapy. However, the underlying regulatory mechanisms of GSK 3β in tumorigenesis remain obscure and require further in-depth investigation. In this review, we comprehensively summarize the roles of GSK 3β in tumorigenesis and oncotherapy, and focus on its potentials as an available target in oncotherapy.

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“…Although the exact mechanism of action is not yet fully clear, experimental studies suggest that the anti-fibrotic properties of tamoxifen are mediated through estrogen receptor (ER)-independent pathways [15]. In this direction, in-vitro studies using human peritoneal mesothelial cells have shown that tamoxifen down-regulates the gene expression of connective-tissue-growth-factor and inhibits the collagen synthesis mediated through the transforming-growth-factor-β (TGF-β) pathway [16,17]. In animal models of PD, administration of tamoxifen is shown to ameliorate the progression of peritoneal thickening and improve peritoneal membrane function through inhibition of the process of mesothelial-tomesenchymal transition [18].…”

Section: Discussionmentioning

confidence: 99%

10-year-long survival in a PD patient with severe calcifying encapsulating peritoneal sclerosis treated with tamoxifen: a case-report

et al. 2020

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Background: Encapsulating-peritoneal-sclerosis (EPS) is a rare, but serious and life-threatening complication of peritoneal dialysis (PD). Treatment of EPS consists of discontinuation of PD and maintenance of nutritional status, whereas the role of corticosteroids, tamoxifen and other immunosuppresive agents is not yet fully elucidated. Case-presentation: We report the case of a 28-year-old patient, who developed a severe form of calcifying EPS after a 6-year-long therapy with automated PD. The clinical presentation was severe with repeated episodes of total bowel obstruction, weight loss and malnutrition that mandated his prolonged hospitalization. Initial treatment included corticosteroids and tamoxifen (20 mg/day) with a clinically meaningful improvement in gastrointestinal function and nutritional status over the first 6-12 months. Corticosteroids were discontinued at 18 months, but owing to persistence of calcifying lesions and peritoneal thickening in repeated computed-tomography (CT) scans, tamoxifen remained unmodified at a low-dose of 20 mg/day for a 10-year-long period. During follow-up, the patient remained symptoms-free in an excellent clinical condition and the CT findings were unchanged. Conclusions: Long-term administration of tamoxifen was not accompanied by any drug-related adverse effects and potentially exerted a beneficial action on down-regulation of inflammatory and fibrotic processes and improvement of gastrointestinal function, nutritional status and overall health-related quality of life.

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Tamoxifen attenuates dialysate-induced peritoneal fibrosis by inhibiting GSK-3β/β-catenin axis activation

Cited by 10 publications

References 38 publications

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

Effects of tranilast on the epithelial-to-mesenchymal transition in peritoneal mesothelial cells

Glycogen synthase kinase 3β in tumorigenesis and oncotherapy (Review)

10-year-long survival in a PD patient with severe calcifying encapsulating peritoneal sclerosis treated with tamoxifen: a case-report

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