scholarly journals Differential roles of Src in transforming growth factor-ß regulation of growth arrest, epithelial-to-mesenchymal transition and cell migration in pancreatic ductal adenocarcinoma cells

2011 ◽  
Vol 38 (3) ◽  
Author(s):  
Ungefroren
Keyword(s):  
Cell Migration ◽  
Growth Factor ◽  
Pancreatic Ductal Adenocarcinoma ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Growth Arrest ◽  
Ductal Adenocarcinoma ◽  
Mesenchymal Transition ◽  
Adenocarcinoma Cells ◽  
Regulation Of Growth

scholarly journals Transforming Growth Factor β/NR4A1-Inducible Breast Cancer Cell Migration and Epithelial-to-Mesenchymal Transition Is p38α (Mitogen-Activated Protein Kinase 14) Dependent

2017 ◽  
Vol 37 (18) ◽  
Author(s):  
Erik Hedrick ◽  
Stephen Safe
Keyword(s):  
Breast Cancer ◽  
Cell Migration ◽  
Growth Factor ◽  
Nuclear Export ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Transforming Growth Factor Β ◽  
Mitogen Activated Protein Kinase ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein

ABSTRACT Transforming growth factor β (TGF-β)-induced migration of triple-negative breast cancer (TNBC) cells is dependent on nuclear export of the orphan receptor NR4A1, which plays a role in proteasome-dependent degradation of SMAD7. In this study, we show that TGF-β induces p38α (mitogen-activated protein kinase 14 [MAPK14]), which in turn phosphorylates NR4A1, resulting in nuclear export of the receptor. TGF-β/p38α and NR4A1 also play essential roles in the induction of epithelial-to-mesenchymal transition (EMT) and induction of β-catenin in TNBC cells, and these TGF-β-induced responses and nuclear export of NR4A1 are blocked by NR4A1 antagonists, the p38 inhibitor SB202190, and kinase-dead [p38(KD)] and dominant-negative [p38(DN)] forms of p38α. Inhibition of NR4A1 nuclear export results in nuclear export of TGF-β-induced β-catenin, which then undergoes proteasome-dependent degradation. TGF-β-induced β-catenin also regulates NR4A1 expression through formation of the β-catenin–TCF-3/TCF-4/LEF-1 complex on the NR4A1 promoter. Thus, TGF-β-induced nuclear export of NR4A1 in TNBC cells plays an essential role in cell migration, SMAD7 degradation, EMT, and induction of β-catenin, and all of these pathways are inhibited by bis-indole-derived NR4A1 antagonists that inhibit nuclear export of the receptor and thereby block TGF-β-induced migration and EMT.

scholarly journals SMAD4 and the TGFβ Pathway in Patients with Pancreatic Ductal Adenocarcinoma

2020 ◽  
Vol 21 (10) ◽  
pp. 3534
Author(s):  
Julie Dardare ◽  
Andréa Witz ◽  
Jean-Louis Merlin ◽  
Pauline Gilson ◽  
Alexandre Harlé
Keyword(s):  
Pancreatic Ductal Adenocarcinoma ◽  
Molecular Mechanisms ◽  
Epithelial To Mesenchymal Transition ◽  
Transforming Growth Factor ◽  
Current Knowledge ◽  
Ductal Adenocarcinoma ◽  
Tgfβ Signaling ◽  
Potent Inducer ◽  
Mesenchymal Transition ◽  
Tgfβ Pathway

Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer death worldwide. PDAC is an aggressive disease with an 11-month median overall survival and a five-year survival of less than 5%. Incidence of PDAC is constantly increasing and is predicted to become the second leading cause of cancer in Western countries within a decade. Despite research and therapeutic development, current knowledge about PDAC molecular mechanisms still needs improvements and it seems crucial to identify novel therapeutic targets. Genomic analyses of PDAC revealed that transforming growth factor β (TGFβ) signaling pathways are modified and the SMAD4 gene is altered in 47% and 60% of cases, respectively, highlighting their major roles in PDAC development. TGFβ can play a dual role in malignancy depending on the context, sometimes as an inhibitor and sometimes as an inducer of tumor progression. TGFβ signaling was identified as a potent inducer of epithelial-to-mesenchymal transition (EMT), a process that confers migratory and invasive properties to epithelial cells during cancer. Therefore, aberrant TGFβ signaling and EMT are linked to promoting PDAC aggressiveness. TGFβ and SMAD pathways were extensively studied but the mechanisms leading to cancer promotion and development still remain unclear. This review aims to describe the complex role of SMAD4 in the TGFβ pathway in patients with PDAC.

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