Resveratrol inhibits transforming growth factor-&amp;beta;2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the Smad pathway

Chen, Ching‐Long; Chen, Yi-Hao; Tai, Ming‐Cheng; Liang, Chang-Min; Lu, Da‐Wen; Chen, Jiann‐Torng

doi:10.2147/dddt.s126743

Cited by 46 publications

(33 citation statements)

References 53 publications

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“…Evidence has shown that RSV suppresses cancer metastasis through inhibiting TGFβ induced EMT . To further delineate the role for TRPM7 in modulating RSV‐mediated inhibition of EMT, we assessed migration of DU145 and PC3 cells with and without TGFβ treatment.…”

Section: Resultsmentioning

confidence: 99%

TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

Sun

Schaar

Sukumaran

et al. 2018

Molecular Carcinogenesis

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Growth factors, such as the transforming growth factor beta (TGFβ), play an important role in promoting metastasis of prostate cancer, thus understanding how TGFβ could induce prostate cancer cell migration may enable us to develop targeted strategies for treatment of advanced metastatic prostate cancer. To more clearly define the mechanism(s) involved in prostate cancer cell migration, we undertook a series of studies utilizing non‐malignant prostate epithelial cells RWPE1 and prostate cancer DU145 and PC3 cells. Our studies show that increased cell migration was observed in prostate cancer cells, which was mediated through epithelial‐to‐mesenchymal transition (EMT). Importantly, addition of Mg2+, but not Ca2+, increased cell migration. Furthermore, TRPM7 expression, which functions as an Mg2+ influx channel, was also increased in prostate cancer cells. Inhibition of TRPM7 currents by 2‐APB, significantly blocked cell migration in both DU145 and PC3 cells. Addition of growth factor TGFβ showed a further increase in cell migration, which was again blocked by the addition of 2‐APB. Importantly, TGFβ addition also significantly increased TRPM7 expression and function, and silencing of TRPM7 negated TGFβ‐induced cell migration along with a decrease in EMT markers showing loss of cell adhesion. Furthermore, resveratrol, which decreases prostate cancer cell migration, inhibited TRPM7 expression and function including TGFβ‐induced cell migration and activation of TRPM7 function. Together, these results suggest that Mg2+ influx via TRPM7 promotes cell migration by inducing EMT in prostate cancer cells and resveratrol negatively modulates TRPM7 function thereby inhibiting prostate cancer metastasis.

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Section: Resultsmentioning

confidence: 99%

TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

Sun

Schaar

Sukumaran

et al. 2018

Molecular Carcinogenesis

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“…Poricoic acid G and poricoic acid H suppressed TGF-β/Smad pathway by selectively inhibiting the phosphorylation of Smad3 via blocking the interactions of SARA with TGFβRI and Smad3 [178]. Similarly, renal fibrosis in a variety of animal models were attenuated or suppressed through TGF-β/Smads and NF-κB-mediated pathways by administration of compounds isolated from various natural products, such as GQ5 [179], arctigenin [98], curcumin [180,181], resveratrol [182], berberine [183,184], sinomenine [185], rutin [186], oxymatrine [149,187], bergenin [188], oleanolic acid [189], tanshinone IIA [190], leonurine [191]; (+/−)-sinensilactam A [192], epigallocatechin-3-gallate [193] and astragaloside IV [194,195].…”

Section: Specific Inhibition Of Smads Signaling By Natural Productsmentioning

confidence: 99%

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Chen

Yang

et al. 2018

Biomedicine & Pharmacotherapy

279

200

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Chronic kidney disease (CKD) has emerged as a major cause of morbidity and mortality worldwide. Interstitial fibrosis, glomerulosclerosis and inflammation play the central role in the pathogenesis and progression of CKD to end stage renal disease (ESRD). Transforming growth factor-β1 (TGF-β1) is the central mediator of renal fibrosis and numerous studies have focused on inhibition of TGF-β1 and its downstream targets for treatment of kidney disease. However, blockade of TGF-β1 has not been effective in the treatment of CKD patients. This may be, in part due to anti-inflammatory effect of TGF-β1. The Smad signaling system plays a central role in regulation of TGF-β1 and TGF-β/Smad pathway plays a key role in progressive renal injury and inflammation. This review provides an overview of the role of TGF-β/Smad signaling pathway in the pathogenesis of renal fibrosis and inflammation and an effective target of anti-fibrotic therapies. Under pathological conditions, Smad2 and Smad3 expression are upregulated, while Smad7 is downregulated. In addition to TGF-β1, other pathogenic mediators such as angiotensin II and lipopolysaccharide activate Smad signaling through both TGF-β-dependent and independent pathways. Smads also interact with other pathways including nuclear factor kappa B (NF-κB) to regulate renal inflammation and fibrosis. In the context of renal fibrosis and inflammation, Smad3 exerts profibrotic effect, whereas Smad2 and Smad7 play renal protective roles. Smad4 performs its dual functions by transcriptionally promoting Smad3-dependent renal fibrosis but simultaneously suppressing NF-κB-mediated renal inflammation via Smad7-dependent mechanism. Furthermore, TGF-β1 induces Smad3 expression to regulate microRNAs and Smad ubiquitination regulatory factor (Smurf) to exert its pro-fibrotic effect. In conclusion, TGF-β/Smad signaling is an important pathway that mediates renal fibrosis and inflammation. Thus, an effective anti-fibrotic therapy via inhibition of Smad3 and upregulation of Smad7 signaling constitutes an attractive approach for treatment of CKD.

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“…Previous work also has indicated that RESV can affect migration of various cancer cells, 24,25 and it has been suggested that RESV may inhibit migration of ARPE-19 retinal epithelial cells. 26 RESV treatment resulted in a significant reduction in transdifferentiation from lens epithelial cells to myofibroblasts. The profibrotic cytokine, TGFb is heavily involved in the development of PCO and EMT in particular.…”

Section: Discussionmentioning

confidence: 92%

Resveratrol Inhibits Wound Healing and Lens Fibrosis: A Putative Candidate for Posterior Capsule Opacification Prevention

Smith

Eldred

Wormstone

2019

Invest. Ophthalmol. Vis. Sci.

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PURPOSE. Posterior capsule opacification (PCO) is a common complication of cataract surgery. In addition to improved surgical methods and IOL designs, it is likely additional agents will be needed to improve patient outcomes. Presently no pharmacological agent is in clinical use to prevent PCO. Here we investigate the putative ability of resveratrol (RESV), a naturally occurring polyphenol, as a therapeutic agent. METHODS. The human lens epithelial cell line FHL124, a human lens capsular bag model, and central anterior epithelium were used as experimental systems. Standard culture was in 5% fetal calf serum Eagle's minimum essential medium; 10 ng/mL transforming growth factor-b2 (TGFb2) was used to induce fibrotic changes. A scratch wound assay was used to measure cell migration and the patch assay was used to assess matrix contraction by FHL124 cells. Protein expression was assessed by immunocytochemistry and Western blot and gene expression by quantitative RT-PCR. In capsular bags, cell growth across the posterior lens capsule, capsular wrinkling, and epithelial-to-mesenchymal transition were determined by image analysis. RESULTS. In FHL124 cells, addition of 30 lM RESV significantly impeded cell migration in a wound-healing assay. RESV significantly inhibited TGFb2-induced expression of the myofibroblast marker alpha-smooth muscle actin (a-SMA) at both the message and protein levels, as well as significantly inhibiting matrix contraction induced by TGFb2. In human capsular bags, 30 lM RESV significantly inhibited cell growth. TGFb2-induced a-SMA expression and capsular wrinkling were also significantly inhibited by RESV treatment. RESV significantly suppressed expression of TGFb2-induced genes associated with fibrotic disease, including matrix metalloproteinase-2 in FHL124 cells, capsular bags, and central anterior epithelium. CONCLUSIONS. RESV can counter PCO-related physiological events in two human lens model systems. RESV therefore has the potential to be used as a candidate agent for the prevention of PCO, which in turn could benefit millions of cataract patients.

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Resveratrol inhibits transforming growth factor-β2-induced epithelial-to-mesenchymal transition in human retinal pigment epithelial cells by suppressing the Smad pathway

Cited by 46 publications

References 53 publications

TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

TGFβ‐induced epithelial‐to‐mesenchymal transition in prostate cancer cells is mediated via TRPM7 expression

Central role of dysregulation of TGF-β/Smad in CKD progression and potential targets of its treatment

Resveratrol Inhibits Wound Healing and Lens Fibrosis: A Putative Candidate for Posterior Capsule Opacification Prevention

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