Matrix Metalloproteinase Inhibitors Suppress Transforming Growth Factor-β-Induced Subcapsular Cataract Formation

Dwivedi, Dhruva J.; Pino, G; Banh, Alice; Nathu, Z.; Howchin, Derek; Margetts, Peter J.; Sivak, J. G.; West‐Mays, Judith A.

doi:10.2353/ajpath.2006.041089

Cited by 65 publications

(62 citation statements)

References 40 publications

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“…Indeed, active TGF-b1 can induce transdifferentiation from fibroblasts to myofibroblasts in the tumour microenvironment, which show an increased expression of various proteolytic enzymes including MMPs (Dwivedi et al, 2006). In turn, these proteases, including plasmin (George et al, 2005), MMP-2 (Wang et al, 2006), MMP-3 (Maeda et al, 2002) and MMP-13 (D'Angelo et al, 2001), have been shown to be involved in TGF-b1 activation.…”

Section: Discussionmentioning

confidence: 99%

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

et al. 2007

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Transforming growth factor-b1 (TGF-b1), a tumour suppressing as well as tumour-promoting cytokine, is stored as an extracellular matrix-bound latent complex. We examined TGF-b1 activation and localisation of TGF-b1 activity in gastric cancer. Gastric tumours showed increased stromal and epithelial total TGF-b1 staining by immunohistochemistry. Active TGF-b1 was present in malignant epithelial cells, but most strongly in smooth muscle actin expressing fibroblasts. Normal gastric mucosa from the same patient showed some staining for total, and little for active TGF-b1. Active TGF-b1 levels were determined by ELISA on tissue homogenates, confirming a strong increase in active TGF-b1 in tumours compared to corresponding normal mucosa. Moreover, high tumour TGFb1 activity levels were significantly associated with clinical parameters, including worse survival of the patients. Total and active TGFb1 levels were not correlated, suggesting a specific activation process. Of the different proteases tested, active TGF-b1 levels were only correlated with urokinase activity levels. The correlation with urokinase activity suggests a role for plasmin in TGF-b1 activation in the tumour microenvironment, resulting in transformation of resident fibroblasts to tumour promoting myofibroblasts. In conclusion we have shown localisation and clinical relevance of TGF-b1 activity levels in gastric cancer.

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Section: Discussionmentioning

confidence: 99%

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

et al. 2007

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“…Similarly, in both murine mammary epithelium and a rat cataract model, E-cadherin ectodomain shedding was found to promote an EMT (18,51). Although the association between EMT and E-cadherin ectodomain shedding has not been extensively evaluated in human cancer models, sE-cad is elevated in the bodily fluids of cancer patients and is associated with poor prognosis or the development of metastasis (12,13,(27)(28)(29).…”

Section: Discussionmentioning

confidence: 99%

Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9–Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells

Symowicz

Adley²,

Gleason³

et al. 2007

Cancer Research

206

228

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Reversible modulation of cell-cell adhesion, cell-matrix adhesion, and proteolytic activity plays a critical role in remodeling of the neoplastic ovarian epithelium during metastasis, implicating cadherins, integrins, and proteinases in i.p. metastatic dissemination of epithelial ovarian carcinoma (EOC). Aberrant epithelial differentiation is an early event in ovarian carcinogenesis; thus, in contrast to most carcinomas that lose E-cadherin expression with progression, E-cadherin is abundant in primary EOC. Metastasizing EOCs engage in integrinmediated adhesion to submesothelial interstitial collagens and express matrix metalloproteinases (MMP) that facilitate collagen invasion, thereby anchoring secondary lesions in the submesothelial matrix. As metalloproteinases have also been implicated in E-cadherin ectodomain shedding, the current study was undertaken to model the effects of matrix-induced integrin clustering on proteinase-catalyzed E-cadherin ectodomain shedding. Aggregation of collagen-binding integrins induced shedding of an 80-kDa E-cadherin ectodomain [soluble E-cadherin (sE-cad)] in a MMP-and Src kinasedependent manner, and sE-cad was prevalent in ascites from ovarian cancer patients. Expression of MMP-9 was elevated by integrin aggregation, integrin-mediated ectodomain shedding was inhibited by a MMP-9 function blocking antibody, and incubation of cells with exogenous MMP-9 catalyzed E-cadherin ectodomain shedding. In contrast to other tumors wherein sE-cad is released into the circulation, EOC tumors maintain direct contact with sE-cad-rich ascites at high concentration, and incubation of EOC cells with physiologically relevant concentrations of recombinant sE-cad disrupted adherens junctions. These data support a novel mechanism for posttranslational modification of E-cadherin function via MMP-9 induction initiated by cell-matrix contact and suggest a mechanism for promotion of EOC metastatic dissemination.

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“…Activation of TGF␤ has also been implicated in multiple fibrotic diseases, including those of the eye, such as glaucoma and anterior subcapsular cataract (35)(36)(37)(38). Moreover, several mechanisms of TGF␤ activation are known (39), and a diverse…”

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confidence: 99%

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

Fatma

Kubo

Takamura

et al. 2009

Journal of Biological Chemistry

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Activation of transforming growth factor ␤ (TGF␤) in response to increased reactive oxygen species (ROS) leads to pathophysiology of cells/tissues by overmodulation of gene transcription. PRDX6 plays a rheostat role in regulating gene transcription by controlling cellular ROS in maintaining homeostasis; thus, fine tuning of Prdx6 expression is required to optimize ROS levels. Ϫ/Ϫ or Prdx6 Ϫ/Ϫ cells was moderately increased by disruption of NF-B sites, suggesting the role of NF-B in tuning of Prdx6 expression. Findings revealed a mechanism of repression and regulation of PRDX6 expression in cells facing stress or aging and provided clues for antioxidant(s)-based new approaches in preventing ROS-driven deleterious signaling. PRDX6 (peroxiredoxin 6) is a member of an emerging peroxiredoxin family that has GSH peroxidase as well as acidic Ca 2ϩ -independent phospholipase A2 activities (1-7). The peroxiredoxins function in concert to detoxify reactive oxygen species (ROS) 2 and play a cytoprotective role by removing ROS and by limiting ROS levels regulating cell survival signaling (1, 3, 4, 6, 8, 9 -11). The unique ability to regulate signaling and to maintain phospholipid turnover distinguishes PRDX6 from the other five peroxiredoxins (PRDX1 to -5). This molecule is widely expressed, occurring in high levels in the liver, lung, eye lens, and keratinocytes (1, 2, 10, 12-18), whereas reduced expression of PRDX6 can lead to cell death and tissue degeneration (10, 11, 15, 19 -22). PRDX6 has been implicated in maintenance of blood vessel integrity in wounded skin (23, 24) and in development and progression of several diseases, including oxidative-induced cataractogenesis (25), psoriasis (12, 26) atherosclerosis (22), and Parkinsonian dementia (27). Accumulating evidence indicates that expression levels of PRDX6 contribute to pathophysiology of cells and tissues. Several studies have reported decreases in antioxidant levels and increases in ROS levels, leading to a decline in a number of physiological functions because of overmodulation of ROS-mediated gene expression and activation of such factors as TGF␤ and NF-B, hallmarks of the aging process and age-associated degenerative diseases (28 -30). However, given the role of ROS as a mediator of normal or redox signaling, we believe that optimal regulation of Prdx6 expression may require fine tuning to avoid overshooting the desired beneficial effects to the point of perturbing the delicate redox balance essential to maintenance of normal cellular function. Recently, using targeted inactivation of the Prdx6 gene, we reported activation and expression of TGF␤ and TGF␤-mediated suppression of Prdx6 mRNA and protein (1,4,5,31), suggesting that this molecule may have a role in repression of Prdx6 transcription. Quantification by staining with H2DCF-DA established a higher prevalence of ROS in these cells. Also, the activation of TGF␤ in Prdx6-deficient cells was associated with ROS and inhibited by PRDX6 overexpression or MnTBAP, a superoxide dismutase mimetic and a known ROS...

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Matrix Metalloproteinase Inhibitors Suppress Transforming Growth Factor-β-Induced Subcapsular Cataract Formation

Cited by 65 publications

References 40 publications

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Tissue level, activation and cellular localisation of TGF-β1 and association with survival in gastric cancer patients

Engagement of Collagen-Binding Integrins Promotes Matrix Metalloproteinase-9–Dependent E-Cadherin Ectodomain Shedding in Ovarian Carcinoma Cells

Loss of NF-κB Control and Repression of Prdx6 Gene Transcription by Reactive Oxygen Species-driven SMAD3-mediated Transforming Growth Factor β Signaling

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