scholarly journals A Twist-Snail Axis Critical for TrkB-Induced Epithelial-Mesenchymal Transition-Like Transformation, Anoikis Resistance, and Metastasis

2009 ◽  
Vol 29 (13) ◽  
pp. 3722-3737 ◽  
Author(s):  
Marjon A. Smit ◽  
Thomas R. Geiger ◽  
Ji-Ying Song ◽  
Inna Gitelman ◽  
Daniel S. Peeper
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Lung Metastases ◽  
Cancer Prognosis ◽  
Mitogen Activated Protein Kinase ◽  
Morphological Transformation ◽  
Anoikis Resistance ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
Growth Of Tumor ◽  
Kinase Pathway

ABSTRACT In a genomewide anoikis suppression screen for metastasis genes, we previously identified the neurotrophic receptor tyrosine kinase TrkB. In mouse xenografts, activated TrkB caused highly invasive and metastatic tumors. Here, we describe that TrkB also induces a strong morphological transformation, resembling epithelial-mesenchymal transition (EMT). This required TrkB kinase activity, a functional mitogen-activated protein kinase pathway, suppression of E-cadherin, and induction of Twist, a transcription factor contributing to EMT and metastasis. RNA interference (RNAi)-mediated Twist depletion blocked TrkB-induced EMT-like transformation, anoikis suppression, and growth of tumor xenografts. By searching for essential effectors of TrkB-Twist signaling, we found that Twist induces Snail, another EMT regulator associated with poor cancer prognosis. Snail depletion impaired EMT-like transformation and anoikis suppression induced by TrkB, but in contrast to Twist depletion, it failed to inhibit tumor growth. Instead, Snail RNAi specifically impaired the formation of lung metastases. Epistasis experiments suggested that Twist acts upstream from Snail. Our results demonstrate that TrkB signaling activates a Twist-Snail axis that is critically involved in EMT-like transformation, tumorigenesis, and metastasis. Moreover, our data shed more light on the epistatic relationship between Twist and Snail, two key transcriptional regulators of EMT and metastasis.

scholarly journals The Roles of Mitogen-Activated Protein Kinase Pathways in TGF-β-Induced Epithelial-Mesenchymal Transition

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Ting Gui ◽  
Yujing Sun ◽  
Aiko Shimokado ◽  
Yasuteru Muragaki
Keyword(s):  
Growth Factors ◽  
Protein Kinase ◽  
Epithelial Mesenchymal Transition ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Important Process ◽  
Mesenchymal Transition ◽  
Mitogen Activated Protein ◽  
And Function ◽  
External Signals

The mitogen-activated protein kinase (MAPK) pathway allows cells to interpret external signals and respond appropriately, especially during the epithelial-mesenchymal transition (EMT). EMT is an important process during embryonic development, fibrosis, and tumor progression in which epithelial cells acquire mesenchymal, fibroblast-like properties and show reduced intercellular adhesion and increased motility. TGF-β signaling is the first pathway to be described as an inducer of EMT, and its relationship with the Smad family is already well characterized. Studies of four members of the MAPK family in different biological systems have shown that the MAPK and TGF-β signaling pathways interact with each other and have a synergistic effect on the secretion of additional growth factors and cytokines that in turn promote EMT. In this paper, we present background on the regulation and function of MAPKs and their cascades, highlight the mechanisms of MAPK crosstalk with TGF-β signaling, and discuss the roles of MAPKs in EMT.

scholarly journals The Novel Mnk1/2 Degrader VNLG-152 Potently Inhibits TNBC Tumor Growth and Metastasis

2018 ◽  
Author(s):  
Senthilmurugan Ramalingam ◽  
Vidya P. Ramamurthy ◽  
Lalji K. Gediya ◽  
Francis N. Murigi ◽  
Puranik Purushottamachar ◽  
...  
Keyword(s):  
Epithelial Mesenchymal Transition ◽  
Critical Role ◽  
Mitogen Activated Protein Kinase ◽  
Initiation Factor ◽  
Mesenchymal Transition ◽  
Eukaryotic Initiation Factor 4E ◽  
Mtorc1 Signaling ◽  
Mitogen Activated Protein ◽  
Orally Bioavailable ◽  
Tumor Growth And Metastasis

ABSTRACTCurrently, there are no effective therapies for patients with triple-negative breast cancer (TNBC), an aggressive and highly metastatic disease. Activation of eukaryotic initiation factor 4E (eIF4E) by mitogen-activated protein kinase (MAPK)-interacting kinases 1 and 2 (Mnk1/2) play a critical role in the development, progression and metastasis of TNBC. Herein, we undertook a comprehensive study to evaluate the activity of a first-in-class Mnk1/2 protein degraders, in clinically relevant models of TNBC. These studies enabled us to identify racemic VNLG-152R as the most efficacious Mnk1/2 degrader. By targeting Mnk1/2 protein degradation (activity), VNLG-152R potently inhibited both Mnk-eIF4E and mTORC1 signaling pathways and strongly regulated downstream factors involved in cell cycle regulation, apoptosis, pro-inflammatory cytokines/chemokines secretion, epithelial-mesenchymal transition (EMT) and metastasis. Most importantly, orally bioavailable VNLG-152R exhibited remarkable antitumor and antimetastatic activities against cell line and patient-derived TNBC xenograft models, with no apparent host toxicity. Collectively, these studies demonstrate that targeting Mnk-eIF4E/mTORC1 signaling with a potent Mnk1/2 degrader, VNLG-152R, is a novel therapeutic strategy that can be developed as monotherapy for effective treatment of patients with primary/metastatic TNBC.

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