Estradiol Induces Epithelial to Mesenchymal Transition of Human Glioblastoma Cells

Hernández-Vega, Ana M; Moral-Morales, Aylin Del; Zamora-Sánchez, Carmen J.; Piña-Medina, Ana Gabriela; González-Arenas, Aliesha

doi:10.3390/cells9091930

Cited by 29 publications

(52 citation statements)

References 121 publications

(135 reference statements)

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“…EMT is activated by several signaling pathways that can cooperate in a cell-type-specific and context-dependent manner to activate the expression of EMT-inducing transcription factors (EMT-TFs), which coordinate epithelial gene repression and mesenchymal gene induction [ 21 ]. Some signaling pathways that activate the EMT-TFs in GBM include those mediated by transforming growth factor β (TGF-β) [ 22 ], receptor tyrosine-kinases (RTKs) [ 23 , 24 , 25 ], wingless-integration (Wnt)/beta-catenin [ 26 , 27 ], hypoxia [ 28 , 29 ], inflammatory cytokines such as interleukin 6 (IL-6) [ 30 ], and steroid hormones such as 17β-estradiol (E2) [ 31 ]. The complexity of the molecular network and the variables in each cell system provoke a partial or intermediate EMT program, resulting in very diverse cellular phenotypes [ 32 ].…”

Section: Introductionmentioning

confidence: 99%

“…Interestingly, high concentrations of E2 and a change in ERs expression levels have been detected in GBM biopsies, suggesting an essential role for these receptors in GBM pathology [ 44 , 45 , 46 , 47 , 48 ]. E2 through ER-α induces EMT in human GBM-derived cells [ 31 ]. EMT program activation by the E2 could vary in the microenvironment of GBM by interacting with the signaling pathways of other inducers of EMT, such as TGF-β.…”

Section: Introductionmentioning

confidence: 99%

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

Hernández-Vega

2021

Brain Sciences

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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.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Hernández-Vega

2021

Brain Sciences

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“…At the same time, the treatment with MPP, an antagonist of ERα, blocked the E2 and PPT effects. The agonist of ERβ, DNP, did not affect any processes [63].…”

Section: Gonadal Steroid Hormones In the Prevalence And Progression Omentioning

confidence: 82%

“…It was also determined that the mRNA expression of ERα and ERβ was higher in the mesenchymal glioblastoma subtype compared to the other three subtypes defined by Verhaak and cols [62]. Besides, using TCGA analysis, a higher expression of both ER subtypes was associated with a poor clinical outcome [63]. On the contrary, Jimenez and cols found that the lowest expression of ERα mRNA was associated with a bad prognosis [64].…”

Section: Gonadal Steroid Hormones In the Prevalence And Progression Omentioning

confidence: 96%

Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

Bello-Álvarez

2021

Biol Sex Differ

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Background As in other types of cancers, sex is an essential factor in the origin and progression of glioblastomas. Research in the field of endocrinology and cancer suggests that gonadal steroid hormones play an important role in the progression and prevalence of glioblastomas. In the present review, we aim to discuss the actions and mechanism triggered by gonadal steroid hormones in glioblastomas. Main body Glioblastoma is the most common malignant primary brain tumor. According to the epidemiological data, glioblastomas are more frequent in men than in women in a 1.6/1 proportion both in children and adults. This evidence, and the knowledge about sex influence over the prevalence of countless diseases, suggest that male gonadal steroid hormones, such as testosterone, promote glioblastomas growth. In contrast, a protective role of female gonadal steroid hormones (estradiol and progesterone) against glioblastomas has been questioned. Several pieces of evidence demonstrate a variety of effects induced by female and male gonadal steroid hormones in glioblastomas. Several studies indicate that pregnancy, a physiological state with the highest progesterone and estradiol levels, accelerates the progression of low-grade astrocytomas to glioblastomas and increases the symptoms associated with these tumors. In vitro studies have demonstrated that progesterone has a dual role in glioblastoma cells: physiological concentrations promote cell proliferation, migration, and invasion while very high doses (out physiological range) reduce cell proliferation and increases cell death. Conclusion Gonadal steroid hormones can stimulate the progression of glioblastomas through the increase in proliferation, migration, and invasion. However, the effects mentioned above depend on the concentrations of these hormones and the receptor involved in hormone actions. Estradiol and progesterone can exert promoter or protective effects while the role of testosterone has been always associated to glioblastomas progression.

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“…They found that in breast cancer cells no expressing ER, P4 induced the activation of cSrc through PR ( 22 ). In glioblastomas, estradiol increased cell growth, migration, invasion, and the epithelial–mesenchymal transition (EMT) through activation of ERα ( 57 , 58 ); therefore, we cannot dismiss the idea of the role of ERα in the PR-cSrc interaction.…”

Section: Discussionmentioning

confidence: 99%

Intracellular Progesterone Receptor and cSrc Protein Working Together to Regulate the Activity of Proteins Involved in Migration and Invasion of Human Glioblastoma Cells

2021

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Glioblastomas are the most common and aggressive primary brain tumors in adults, and patients with glioblastoma have a median survival of 15 months. Some alternative therapies, such as Src family kinase inhibitors, have failed presumably because other signaling pathways compensate for their effects. In the last ten years, it has been proven that sex hormones such as progesterone (P4) can induce growth, migration, and invasion of glioblastoma cells through its intracellular progesterone receptor (PR), which is mostly known for its role as a transcription factor, but it can also induce non-genomic actions. These non-classic actions are, in part, a consequence of its interaction with cSrc, which plays a significant role in the progression of glioblastomas. We studied the relation between PR and cSrc, and its effects in human glioblastoma cells. Our results showed that P4 and R5020 (specific PR agonist) activated cSrc protein since both progestins increased the p-cSrc (Y416)/cSrc ratio in U251 and U87 human glioblastoma derived cell lines. When siRNA against the PR gene was used, the activation of cSrc by P4 was abolished. The co-immunoprecipitation assay showed that cSrc and PR interact in U251 cells. P4 treatment also promoted the increase in the p-Fak (Y397) (Y576/577)/Fak and the decrease in p-Paxillin (Y118)/Paxillin ratio, which are significant components of the focal adhesion complex and essential for migration and invasion processes. A siRNA against cSrc gene blocked the increase in the p-Fak (Y576/Y577)/Fak ratio and the migration induced by P4, but not the decrease in p-Paxillin (Y118)/Paxillin ratio. We analyzed the potential role of cSrc over PR phosphorylation in three databases, and one putative tyrosine residue in the amino acid 87 of PR was found. Our results showed that P4 induces the activation of cSrc protein through its PR. The latter and cSrc could interact in a bidirectional mode for regulating the activity of proteins involved in migration and invasion of glioblastomas.

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Estradiol Induces Epithelial to Mesenchymal Transition of Human Glioblastoma Cells

Cited by 29 publications

References 121 publications

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

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

Impact of sex in the prevalence and progression of glioblastomas: the role of gonadal steroid hormones

Intracellular Progesterone Receptor and cSrc Protein Working Together to Regulate the Activity of Proteins Involved in Migration and Invasion of Human Glioblastoma Cells

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