Estrogen regulates excitatory amino acid carrier 1 (EAAC1) expression through sphingosine kinase 1 (SphK1) transacting FGFR-mediated ERK signaling in rat C6 astroglial cells

Huang, Cui; Yuan, Peng; Wu, Jing; Huang, Jia

doi:10.1016/j.neuroscience.2016.01.027

Cited by 10 publications

(9 citation statements)

References 62 publications

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“…To the best of our knowledge there is no data suggesting any crosstalk between PTTG and GPER1. On the other hand, a few studies in breast cancer cells showed that estrogen stimulates FGF2 transcription via binding to GPER1 [52,53]. Our results might indicate that a mechanism similar to that seen in breast cancer exists in pituitary tumors, where GPER1 along with aromatase and classical ERs mediate estrogen effects such as tumor promotion via upregulation of PTTG and FGF2.…”

Section: Discussionsupporting

confidence: 54%

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

Özkaya

Sayitoğlu

Çomunoğlu

et al. 2020

Exp Clin Endocrinol Diabetes

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Purpose To evaluate the expression of G-protein coupled estrogen receptor (GPER1), aromatase, estrogen receptor α (ERα), estrogen receptor β (ERβ), pituitary tumor transforming gene (PTTG), and fibroblast growth factor 2 (FGF2) in GH-secreting and non-functioning adenomas (NFA). Methods Thirty patients with acromegaly and 27 patients with NFA were included. Gene expression was determined via quantitative reverse transcription polymerase chain reaction (QRT-PCR). Protein expression was determined via immunohistochemistry. Results There was no difference, in terms of gene expression of aromatase, ERα, PTTG, and FGF2 between the two groups (p>0.05 for all). ERβ gene expression was higher and GPER1 gene expression was lower in GH-secreting adenomas than NFAs (p<0.05 for all). Aromatase and ERβ protein expression was higher in GH-secreting adenomas than NFAs (p=0.01). None of the tumors expressed ERα. GPER1 expression was detected in 62.2% of the GH-secreting adenomas and 45% of NFAs. There was no difference in terms of GPER1, PTTG, FGF2 H scores between the two groups (p>0.05 for all). GPER1 gene expression was positively correlated to ERα, ERβ, PTTG, and FGF2 gene expression (p<0.05 for all). There was a positive correlation between aromatase and GPER1 protein expression (r=0.31; p=0.04). Conclusions GPER1 is expressed at both gene and protein level in a substantial portion of GH-secreting adenomas and NFAs. The finding of a positive correlation between GPER1 and ERα, ERβ, PTTG, and FGF2 gene expression and aromatase and GPER1 protein expression suggests GPER1 along with aromatase and classical ERs might mediate the effects of estrogen through upregulation of PTTG and FGF2.

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Section: Discussionsupporting

confidence: 54%

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

Özkaya

Sayitoğlu

Çomunoğlu

et al. 2020

Exp Clin Endocrinol Diabetes

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“…(4) Estrogen modulates S1P production in cells including astroglia, breast, and endothelium. (5)(6)(7) In bone, estrogen is essential for skeletal development and maintenance with a mixture of direct and indirect effects on growth and on the balance of bone formation and resorption. (8) The relation of estrogen and S1P signaling in bone is poorly studied.…”

Section: B Alanced Bone Formation By Osteoblasts and Bone Resorptionmentioning

confidence: 99%

“…Circulating S1P in humans is associated with a negative effect on bone mass, although S1P in osteoblasts promotes growth and survival . Estrogen modulates S1P production in cells including astroglia, breast, and endothelium . In bone, estrogen is essential for skeletal development and maintenance with a mixture of direct and indirect effects on growth and on the balance of bone formation and resorption .…”

Section: Introductionmentioning

confidence: 99%

Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in Human Osteoblasts

et al. 2018

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Production of sphingosine-1-phosphate (S1P) is linked to 17β-estradiol (E2) activity in many estrogen-responsive cells; in bone development, the role of S1P is unclear. We studied effects of S1P on proliferation and differentiation of human osteoblasts (hOB). Ten nM E2, 1 μM S1P, or 1 μM of the S1P receptor 1 (S1PR1) agonist SEW2871 increased hOB proliferation at 24 hours. S1PR 1, 2, and 3 mRNAs are expressed by hOB but not S1PR4 or S1PR5. Expression of S1PR2 was increased at 7 and 14 days of differentiation, in correspondence with osteoblast-related mRNAs. Expression of S1PR1 was increased by E2 or S1P in proliferating hOB, whereas S1PR2 mRNA was unaffected in proliferating cells; S1PR3 was not affected by E2 or S1P. Inhibiting sphingosine kinase (SPHK) activity with sphingosine kinase inhibitor (Ski) greatly reduced the E2 proliferative effect. Both E2 and S1P increased SPHK mRNA at 24 hours in hOB. S1P promoted osteoblast proliferation via activating MAP kinase activity. Either E2 or S1P increased S1P synthesis in a fluorescent S1P assay. Interaction of E2 and S1P signaling was indicated by upregulation of E2 receptor mRNA after S1P treatment. E2 and S1P also promoted alkaline phosphatase expression. During osteoblast differentiation, S1P increased bone-specific mRNAs, similarly to the effects of E2. However, E2 and S1P showed differences in the activation of some osteoblast pathways. Pathway analysis by gene expression arrays was consistent with regulation of pathways of osteoblast differentiation; collagen and cell adhesion proteins centered on Rho/Rac small GTPase signaling and Map kinase or signal transducer and activator of transcription (Stat) intermediates. Transcriptional activation also included significant increases in superoxide dismutase 1 and 2 transcription by either S1P or E2. We demonstrate that the SPHK system is a co-mediator for osteoblast proliferation and differentiation, which is mainly, but not entirely, complementary to E2, whose effects are mediated by S1PR1 and S1PR2.

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“…Likewise, increased FGF2 levels have been observed in plasma samples of patients affected by diverse malignancies, such as leukemia and lung and breast cancers, especially when metastases are present [16,17]. Among diverse stimuli, FGF2 expression and secretion can be regulated by estrogens [18,19], which act mainly through the classical estrogen receptors (ER)α and ERβ leading to the proliferation, migration and survival of breast cancer cells [20]. The G protein estrogen receptor (GPER, also called GPR30) has been identified as a further receptor able to mediate the action of estrogens in numerous pathophysiological conditions [21,22].…”

Section: Introductionmentioning

confidence: 99%

“…Recent studies have shown that a functional interaction between ER and FGFR-mediated pathways may occur toward breast cancer progression, indicating that the simultaneous inhibition of both receptors could be considered in more comprehensive treatments [11,32,33]. GPER was also involved in the estrogen-induced regulation of FGF2 toward the autocrine stimulation of the cognate receptor FGFR1 in astroglial cells [19].…”

Section: Introductionmentioning

confidence: 99%

GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression

Santolla

Vivacqua

Lappano

et al. 2019

Cells

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The FGF2/FGFR1 paracrine loop is involved in the cross-talk between breast cancer cells and components of the tumor stroma as cancer-associated fibroblasts (CAFs). By quantitative PCR (qPCR), western blot, immunofluorescence analysis, ELISA and ChIP assays, we demonstrated that 17β-estradiol (E2) and the G protein estrogen receptor (GPER) agonist G-1 induce the up-regulation and secretion of FGF2 via GPER together with the EGFR/ERK/c-fos/AP-1 signaling cascade in (ER)-negative primary CAFs. Evaluating the genetic alterations from METABRIC and TCGA datasets, we then assessed that FGFR1 is the most frequently amplified FGFRs family member and its amplification/expression associates with shorter survival rates in breast cancer patients. Therefore, in order to assess the functional FGF2/FGFR1 interplay between CAFs and breast cancer cells, we generated the FGFR1-knockout MDA-MB-231 cells using CRISPR/Cas9 genome editing strategy. Using conditioned medium from estrogen-stimulated CAFs, we established that the activation of FGF2/FGFR1 paracrine signaling triggers the expression of the connective tissue growth factor (CTGF), leading to the migration and invasion of MDA-MB-231 cells. Our findings shed new light on the role elicited by estrogens through GPER in the activation of the FGF2/FGFR1 signaling. Moreover, our findings may identify further biological targets that could be considered in innovative combination strategies halting breast cancer progression.

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Estrogen regulates excitatory amino acid carrier 1 (EAAC1) expression through sphingosine kinase 1 (SphK1) transacting FGFR-mediated ERK signaling in rat C6 astroglial cells

Cited by 10 publications

References 62 publications

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

G-protein Coupled Estrogen Receptor Expression in Growth Hormone Secreting and Non-Functioning Adenomas

Sphingosine‐1‐Phosphate Modulates the Effect of Estrogen in Human Osteoblasts

GPER Mediates a Feedforward FGF2/FGFR1 Paracrine Activation Coupling CAFs to Cancer Cells toward Breast Tumor Progression

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