scholarly journals Redox Regulation of NOX Isoforms on FAK(Y397)/SRC(Y416) Phosphorylation Driven Epithelial-to-Mesenchymal Transition in Malignant Cervical Epithelial Cells

Cells ◽  
2020 ◽  
Vol 9 (6) ◽  
pp. 1555
Author(s):  
Young Mee Kim ◽  
Karthika Muthuramalingam ◽  
Moonjae Cho
Keyword(s):  
Growth Factor ◽  
Cancer Progression ◽  
Cellular Localization ◽  
Redox Regulation ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Migration And Invasion ◽  
Mesenchymal Transition ◽  
Tgf Β1 ◽  
Src Pathway

Epithelial-to-mesenchymal transition (EMT) promulgates epithelial cell associated disease-defining characteristics in tumorigenesis and organ fibrosis. Growth factors such as epidermal growth factor and fibroblast growth factor in addition to cytokines such as transforming growth factor-β1 (TGF-β1) is said to play a prominent role in remodeling related pathological events of cancer progression such as invasion, metastasis, apoptosis, EMT, etc. through redox related cellular secondary messengers, in particular the reactive oxygen species (ROS). However, the signaling cascade underlying the redox mechanism and thereby the progression of EMT remains largely unknown. In this study, upon TGF-β1 treatment, we observed an induction in NOX isoforms—NOX2 and NOX4—that have time (early and late) and cellular localization (nucleus and autophagosome co-localized) dependent effects in mediating EMT associated cell proliferation and migration through activation of the focal adhesion kinase (FAK)/SRC pathway in HeLa, human cervical cancer cells. Upon silencing NOX2/4 gene expression and using the SRC inhibitor (AZD0530), progression of TGF-β1 induced EMT related cellular remodeling, extra cellular matrix (ECM) production, cell migration and invasion, got significantly reverted. Together, these results indicate that NOX2 and NOX4 play important, albeit distinct, roles in the activation of cytokine mediated EMT and its associated processes via tyrosine phosphorylation of the FAK/SRC pathway.

scholarly journals Inhibition of Transforming Growth Factor-β1–induced Signaling and Epithelial-to-Mesenchymal Transition by the Smad-binding Peptide Aptamer Trx-SARA

2006 ◽  
Vol 17 (9) ◽  
pp. 3819-3831 ◽  
Author(s):  
Bryan M. Zhao ◽  
F. Michael Hoffmann
Keyword(s):  
Growth Factor ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Receptor Activation ◽  
Binding Motif ◽  
Mesenchymal Transition ◽  
Smad Protein ◽  
Peptide Aptamer ◽  
Tgf Β1

Overexpression of the inhibitory Smad, Smad7, is used frequently to implicate the Smad pathway in cellular responses to transforming growth factor β (TGF-β) signaling; however, Smad7 regulates several other proteins, including Cdc42, p38MAPK, and β-catenin. We report an alternative approach for more specifically disrupting Smad-dependent signaling using a peptide aptamer, Trx-SARA, which comprises a rigid scaffold, the Escherichia coli thioredoxin A protein (Trx), displaying a constrained 56-amino acid Smad-binding motif from the Smad anchor for receptor activation (SARA) protein. Trx-SARA bound specifically to Smad2 and Smad3 and inhibited both TGF-β–induced reporter gene expression and epithelial-to-mesenchymal transition in NMuMG murine mammary epithelial cells. In contrast to Smad7, Trx-SARA had no effect on the Smad2 or 3 phosphorylation levels induced by TGF-β1. Trx-SARA was primarily localized to the nucleus and perturbed the normal cytoplasmic localization of Smad2 and 3 to a nuclear localization in the absence of TGF-β1, consistent with reduced Smad nuclear export. The key mode of action of Trx-SARA was to reduce the level of Smad2 and Smad3 in complex with Smad4 after TGF-β1 stimulation, a mechanism of action consistent with the preferential binding of SARA to monomeric Smad protein and Trx-SARA-mediated disruption of active Smad complexes.

scholarly journals Ketamine-induced bladder fibrosis involves epithelial-to-mesenchymal transition mediated by transforming growth factor-β1

2017 ◽  
Vol 313 (4) ◽  
pp. F961-F972 ◽  
Author(s):  
Junpeng Wang ◽  
Yang Chen ◽  
Di Gu ◽  
Guihao Zhang ◽  
Jiawei Chen ◽  
...  
Keyword(s):  
Growth Factor ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Smooth Muscle Actin ◽  
Bladder Wall ◽  
Transforming Growth Factor Β1 ◽  
Sprague Dawley ◽  
Mesenchymal Transition ◽  
Tgf Β1

Bladder wall fibrosis is a major complication of ketamine-induced cystitis (KC), but the underlying pathogenesis is poorly understood. The aim of the present study was to elucidate the mechanism of ketamine-induced fibrosis in association with epithelial-to-mesenchymal transition (EMT) mediated by transforming growth factor-β1 (TGF-β1). Sprague-Dawley rats were randomly distributed into four groups, which received saline, ketamine, ketamine combined with a TGF-β receptor inhibitor (SB-505124) for 16 wk, or 12 wk of ketamine and 4 wk of abstinence. In addition, the profibrotic effect of ketamine was confirmed in SV-40 immortalized human uroepithelial (SV-HUC-1) cells. The ketamine-treated rats displayed voiding dysfunction and decreased bladder compliance. Bladder fibrosis was accompanied by the appearance of a certain number of cells expressing both epithelial and mesenchymal markers, indicating that epithelial cells might undergo EMT upon ketamine administration. Meanwhile, the expression level of TGF-β1 was significantly upregulated in the urothelium of bladders in ketamine-treated rats. Treatment of SV-HUC-1 cells with ketamine increased the expression of TGF-β1 and EMT-inducing transcription factors, resulting in the downregulation of E-cadherin and upregulation of fibronectin and α-smooth muscle actin. Administration of SB-505124 inhibited EMT and fibrosis both in vitro and vivo. In addition, withdrawal from ketamine did not lead to recovery of bladder urinary function or decreased fibrosis. Taken together, our study shows for the first time that EMT might contribute to bladder fibrosis in KC. TGF-β1 may have an important role in bladder fibrogenesis via an EMT mechanism.

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