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

Abstract

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.

MicroRNA Interrelated Epithelial Mesenchymal Transition (EMT) in Glioblastoma

“…Previous studies showed that E2 induces cell proliferation and the expression of genes involved in mitochondrial metabolism in glioblastomas [ 29 ]. The treatment of glioblastoma cells with E2 resulted in decreased expression of the TGF-β intracellular signaling proteins R-Smads [ 30 ]. In another study, TGF-β1 induced activation of the Wnt/β-catenin pathway during the EMT processes.…”

Evolution of 3-(4-hydroxyphenyl)indoline-2-one as a scaffold for potent and selective anticancer activity

“…However, we now know that many of these reported ERα-negative cell lines actually do express low/extremely low levels of ERα ( e.g. MDA-MB-468/453, 65,66 SK-BR-3, 67 U87MG, 68,69 OVCAR-3 (ref. 70 and 71)).…”

“…SK-BR-3, 67 U87MG,68,69 OVCAR-3 (ref.70 and 71)). When looking at the in vivo tumor models reported in the work, TOP216 shows efficacy in models that all express ERα (MCF-7,72 PC-3,73,74 MDA-MB-468,65,66 MiaPaca,75 and A2780 (ref.71 and 76)).…”

Analysis of U87 glioma cells by dielectrophoresis

“…Understanding characteristic features of glioma cells emerges as an important path to reveal the heterogeneity of GBM microenvironment to provide therapeutic approaches that successfully target the right subsets of glioma cells in GBM and eventually maximize efficacy and minimize the side effects of the applied therapy [5][6][7][8]. Glioma cells display striking cellular heterogeneity by changing their morphology [9][10][11], nuclear volume [12][13][14], cell-cell adhesion [15,16], cellular interaction [17], cytoskeleton organization [18][19][20][21], and by performing epithelial-to-mesenchymal transitions [22][23][24][25][26]. To characterize dynamic variations of glioma cells in the GBM microenvironment without altering genetic and phenotypic properties of the cells, we need to develop adequate tools [10].…”

“…Recent studies have demonstrated effective tools to investigate mostly mechanical properties of glioma cells using fluorescence microscopy [15][16][17][18][19][20][21][22][23][24][25][26][27], 2-photon imaging [11,28], atomic force microscopy [16,29,30], single-cell force spectroscopy [16], and microfluidic technologies [31][32][33][34][35][36][37][38][39]. In contrast to mechanical features, electrical properties of glioma cells have not been extensively interrogated.…”