scholarly journals Crosstalk between 17β-Estradiol and TGF-β Signaling Modulates Glioblastoma Progression

2021 ◽  
Vol 11 (5) ◽  
pp. 564
Author(s):  
Ana M. Hernández-Vega ◽  
Ignacio Camacho-Arroyo
Keyword(s):  
Signaling Pathways ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Morphological Changes ◽  
Transforming Growth Factor Β ◽  
Vimentin Expression ◽  
Mesenchymal Transition ◽  
17Β Estradiol ◽  
Human Gbm

Epithelial–mesenchymal transition (EMT) is an essential mechanism contributing to glioblastoma multiforme (GBM) progression, the most common and malignant brain tumor. EMT is induced by signaling pathways that crosstalk and regulate an intricate regulatory network of transcription factors. It has been shown that downstream components of 17β-estradiol (E2) and transforming growth factor β (TGF-β) signaling pathways crosstalk in estrogen-sensitive tumors. However, little is known about the interaction between the E2 and TGF-β signaling components in brain tumors. We have investigated the relationship between E2 and TGF-β signaling pathways and their effects on EMT induction in human GBM-derived cells. Here, we showed that E2 and TGF-β negatively regulated the expression of estrogen receptor α (ER-α) and Smad2/3. TGF-β induced Smad2 phosphorylation and its subsequent nuclear translocation, which E2 inhibited. Both TGF-β and E2 induced cellular processes related to EMT, such as morphological changes, actin filament reorganization, and mesenchymal markers (N-cadherin and vimentin) expression. Interestingly, we found that the co-treatment of E2 and TGF-β blocked EMT activation. Our results suggest that E2 and TGF-β signaling pathways interact through ER-α and Smad2/3 mediators in cells derived from human GBM and inhibit EMT activation induced by both factors alone.

scholarly journals The Molecular Mechanism of Epithelial–Mesenchymal Transition for Breast Carcinogenesis

Biomolecules ◽  
2019 ◽  
Vol 9 (9) ◽  
pp. 476 ◽  
Author(s):  
Chia-Jung Li ◽  
Pei-Yi Chu ◽  
Giou-Teng Yiang ◽  
Meng-Yu Wu
Keyword(s):  
Epithelial Cells ◽  
Tumor Progression ◽  
Signaling Pathways ◽  
Intracellular Signaling ◽  
Molecular Mechanisms ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Inhibition Of Proliferation ◽  
Mesenchymal Transition

The transforming growth factor-β (TGF-β) signaling pathway plays multiple regulatory roles in the tumorigenesis and development of cancer. TGF-β can inhibit the growth and proliferation of epithelial cells and induce apoptosis, thereby playing a role in inhibiting breast cancer. Therefore, the loss of response in epithelial cells that leads to the inhibition of cell proliferation due to TGF-β is a landmark event in tumorigenesis. As tumors progress, TGF-β can promote tumor cell invasion, metastasis, and drug resistance. At present, the above-mentioned role of TGF-β is related to the interaction of multiple signaling pathways in the cell, which can attenuate or abolish the inhibition of proliferation and apoptosis-promoting effects of TGF-β and enhance its promotion of tumor progression. This article focuses on the molecular mechanisms through which TGF-β interacts with multiple intracellular signaling pathways in tumor progression and the effects of these interactions on tumorigenesis.

scholarly journals Microparticles as Potential Mediators of High Glucose-Induced Renal Cell Injury

Biomolecules ◽  
2019 ◽  
Vol 9 (8) ◽  
pp. 348 ◽  
Author(s):  
Ravindran ◽  
Pasha ◽  
Agouni ◽  
Munusamy
Keyword(s):  
Er Stress ◽  
Signaling Pathways ◽  
Transforming Growth Factor Beta ◽  
High Glucose ◽  
Cell Injury ◽  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Smooth Muscle Actin ◽  
Mesenchymal Transition

Diabetic nephropathy (DN) is the most common cause of chronic kidney disease worldwide. Activation of signaling pathways such as the mammalian target of rapamycin (mTOR), extracellular signal-regulated kinases (ERK), endoplasmic reticulum (ER) stress, transforming growth factor-beta (TGF-β), and epithelial-mesenchymal transition (EMT), are thought to play a significant role in the etiology of DN. Microparticles (MPs), the small membrane vesicles containing bioactive signals shed by cells upon activation or during apoptosis, are elevated in diabetes and were identified as biomarkers in DN. However, their exact role in the pathophysiology of DN remains unclear. Here, we examined the effect of MPs shed from renal proximal tubular cells (RPTCs) exposed to high glucose conditions on naïve RPTCs in vitro. Our results showed significant increases in the levels of phosphorylated forms of 4E-binding protein 1 and ERK1/2 (the downstream targets of mTOR and ERK pathways), phosphorylated-eIF2α (an ER stress marker), alpha smooth muscle actin (an EMT marker), and phosphorylated-SMAD2 and nuclear translocation of SMAD4 (markers of TGF-β signaling). Together, our findings indicate that MPs activate key signaling pathways in RPTCs under high glucose conditions. Pharmacological interventions to inhibit shedding of MPs from RPTCs might serve as an effective strategy to prevent the progression of DN.

scholarly journals Salt-inducible kinases (SIKs) regulate TGFβ-mediated transcriptional and apoptotic responses

2019 ◽  
Author(s):  
Luke D. Hutchinson ◽  
Nicola J. Darling ◽  
Stephanos Nicolaou ◽  
Ilaria Gori ◽  
Daniel R. Squair ◽  
...  
Keyword(s):  
Transforming Growth Factor ◽  
Nuclear Translocation ◽  
Epithelial Mesenchymal Transition ◽  
Apoptotic Cell ◽  
Transforming Growth Factor Β ◽  
Transcriptional Responses ◽  
Mesenchymal Transition ◽  
Smad Phosphorylation ◽  
Tgfβ Signalling ◽  
Pai 1

AbstractThe signalling pathways initiated by members of the transforming growth factor-β (TGFβ) family of cytokines control many metazoan cellular processes, including proliferation and differentiation, epithelial-mesenchymal transition (EMT), and apoptosis. TGFβ signalling is therefore strictly regulated to ensure appropriate context-dependent physiological responses. In an attempt to identify novel regulatory components of the TGFβ signalling pathway, we performed a pharmacological screen using a cell line engineered to report the endogenous transcription of the TGFβ-responsive target gene PAI-1. The screen revealed that small-molecular inhibitors of salt-inducible kinases (SIKs) attenuate TGFβ-mediated transcription of PAI-1 without affecting receptor-mediated SMAD phosphorylation, SMAD complex formation or nuclear translocation. We provide evidence that genetic inactivation of SIK isoforms also attenuates TGFβ-dependent transcriptional responses. Pharmacological inhibition of SIKs using multiple small-molecule inhibitors potentiated apoptotic cell death induced by TGFβ stimulation. Our data therefore provides evidence for a novel function of SIKs in modulating TGFβ-mediated transcriptional and cellular responses.

scholarly journals Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

2018 ◽  
Vol 19 (11) ◽  
pp. 3672 ◽  
Author(s):  
Yutaro Tsubakihara ◽  
Aristidis Moustakas
Keyword(s):  
Growth Factor ◽  
Tumor Cells ◽  
Transforming Growth Factor ◽  
Epithelial Mesenchymal Transition ◽  
Transforming Growth Factor Β ◽  
Basement Membranes ◽  
The Body ◽  
Common Denominator ◽  
Adhesion Forces ◽  
Mesenchymal Transition

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

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