The Src family kinase inhibitors PP2 and PP1 effectively block TGF-beta1-induced cell migration and invasion in both established and primary carcinoma cells

Bartscht, Tobias; Lehnert, Hendrik; Gieseler, Frank; Ungefroren, Hendrik

doi:10.1007/s00280-012-1904-0

Cited by 26 publications

(18 citation statements)

References 27 publications

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“…Moreover, SMURF2 knockout mice are prone to developing a variety of types of cancers including lung cancer; therefore, SMURF2 has been identified as a bona fide tumour suppressor49. In addition, PP1c could function as an important kinase inhibitor of the TGF-β pathway and block tumorigenesis and migration50. These previous findings have highlighted the importance of a regulatory network of β-catenin and TGF-β signalling in the course of NSCLC development and progression.…”

Section: Discussionmentioning

confidence: 94%

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

et al. 2017

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Cancer chemoresistance and metastasis are tightly associated features. However, whether they share common molecular mechanisms and thus can be targeted with one common strategy remain unclear in non-small cell lung cancer (NSCLC). Here, we report that high levels of microRNA-128-3p (miR-128-3p) is key to concomitant development of chemoresistance and metastasis in residual NSCLC cells having survived repeated chemotherapy and correlates with chemoresistance, aggressiveness and poor prognosis in NSCLC patients. Mechanistically, miR-128-3p induces mesenchymal and stemness-like properties through downregulating multiple inhibitors of Wnt/β-catenin and TGF-β pathways, leading to their overactivation. Importantly, antagonism of miR-128-3p potently reverses metastasis and chemoresistance of highly malignant NSCLC cells, which could be completely reversed by restoring Wnt/β-catenin and TGF-β activities. Notably, correlations among miR-128-3p levels, activated β-catenin and TGF-β signalling, and pro-epithelial-to-mesenchymal transition/pro-metastatic protein levels are validated in NSCLC patient specimens. These findings suggest that miR-128-3p might be a potential target against both metastasis and chemoresistance in NSCLC.

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Section: Discussionmentioning

confidence: 94%

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

et al. 2017

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“…The migration assays were performed as decribed previously by us and others [49–51]. Each condition was performed in triplicate or quadruplicate with a programmed signal detection (RTCA software version 1.2.1., OLS, Bremen, Germany) every 15 min for a total of 12-48 h, depending on cell type and setup mode (migration or invasion).…”

Section: Methodsmentioning

confidence: 99%

“…Each condition was performed in triplicate or quadruplicate with a programmed signal detection (RTCA software version 1.2.1., OLS, Bremen, Germany) every 15 min for a total of 12-48 h, depending on cell type and setup mode (migration or invasion). The setup of the invasion assay was identical to that of the migration assay except that the bottom of the wells was covered with a thin layer of Matrigel (5% (v/v), growth factor-reduced, BD Biosciences, Heidelberg, Germany, diluted 1:20 with basal medium) before cell seeding [49]. TGF-β1 was added to both lower and upper wells at the same concentration.…”

Section: Methodsmentioning

confidence: 99%

Proteinase-activated receptor 2 promotes TGF-β-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-β type I receptor ALK5

et al. 2016

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Pancreatic ductal adenocarcinoma (PDAC) is characterized by high expression of transforming growth factor (TGF)-β and the G protein-coupled receptor proteinase-activated receptor 2 (PAR2), the latter of which functions as a cell-surface sensor for serine proteinases asscociated with the tumour microenvironment. Since TGF-β and PAR2 affect tumourigenesis by regulating migration, invasion and metastasis, we hypothesized that there is signalling crosstalk between them. Depleting PDAC and non-PDAC cells of PAR2 by RNA interference strongly decreased TGF-β1-induced activation of Smad2/3 and p38 mitogen-activated protein kinase, Smad dependent transcriptional activity, expression of invasion associated genes, and cell migration/invasion in vitro. Likewise, the plasminogen activator-inhibitor 1 gene in primary cultures of aortic smooth muscle cells from PAR2−/− mice displayed a greatly attenuated sensitivity to TGF-β1 stimulation. PAR2 depletion in PDAC cells resulted in reduced protein and mRNA levels of the TGF-β type I receptor activin receptor-like kinase 5 (ALK5). Forced expression of wild-type ALK5 or a kinase-active ALK5 mutant, but not a kinase-active but Smad-binding defective ALK5 mutant, was able to rescue TGF-β1-induced Smad3 activation, Smad dependent transcription, and cell migration in PAR2-depleted cells. Together, our data show that PAR2 is crucial for TGF-β1-induced cell motility by its ability to sustain expression of ALK5. Therapeutically targeting PAR2 may thus be a promising approach in preventing TGF-β-dependent driven metastatic dissemination in PDAC and possibly other stroma-rich tumour types.

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“…Although it is known that Src can be activated by interaction with integrins1925282930, the specific role of osteopontin receptor, integrin αV, on Src activation in the context of pro-fibrotic response has not been particularly investigated. We investigated the interaction among Src and integrin αV by using coimmunoprecipitation assays (Fig.…”

Section: Resultsmentioning

confidence: 99%

Interaction of Src and Alpha-V Integrin Regulates Fibroblast Migration and Modulates Lung Fibrosis in A Preclinical Model of Lung Fibrosis

Zhao

et al. 2017

Sci Rep

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Src kinase is known to regulate fibroblast migration. However, the contribution of integrin and Src kinase interaction to lung fibrosis has not been mechanistically investigated. Our data demonstrate that integrin alpha v (αV) recruited Src kinase and that leads to subsequent Src activation in fibroblasts plated on fibrotic matrix, osteopontin. Src interaction with integrin αV is required for integrin αV-mediated Src activation, and the subsequent fibroblast migration. The study identified that β5 and β3 are the major integrins for this effect on osteopontin. In contrast, integrins β1, β6, and β8 did not have a critical role in this phenomenon. Importantly, Src inhibitor significantly reduces fibroblast migration stimulated by PDGF-BB and reduced in vivo lung fibrosis in mice. Src inhibitor reduced Src activation and blocked the signaling transduction by integrin αV, inhibited migration signaling pathways and reduced extracellular matrix protein production, and blocked myofibroblast differentiation in vivo in mouse lung tissues. The present study supports that the interaction of Src Kinase and integrins plays a critical role in the development of lung fibrosis and the signaling involved may present a novel opportunity to target deadly fibrotic diseases.

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The Src family kinase inhibitors PP2 and PP1 effectively block TGF-beta1-induced cell migration and invasion in both established and primary carcinoma cells

Cited by 26 publications

References 27 publications

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

Simultaneous overactivation of Wnt/β-catenin and TGFβ signalling by miR-128-3p confers chemoresistance-associated metastasis in NSCLC

Proteinase-activated receptor 2 promotes TGF-β-dependent cell motility in pancreatic cancer cells by sustaining expression of the TGF-β type I receptor ALK5

Interaction of Src and Alpha-V Integrin Regulates Fibroblast Migration and Modulates Lung Fibrosis in A Preclinical Model of Lung Fibrosis

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