scholarly journals ERα-Targeting PROTAC as a Chemical Knockdown Tool to Investigate the Estrogen Receptor Function in Rat Menopausal Arthritis

2021 ◽  
Vol 12 ◽  
Author(s):  
Li Duan ◽  
Xiao Xu ◽  
Limei Xu ◽  
Caining Wen ◽  
Kan Ouyang ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Gene Knockouts ◽  
Matrix Metabolism ◽  
Or Gene ◽  
Genetic Compensation ◽  
Embryonic Death

Proteolytic targeting chimeras (PROTACs) is a rapid and reversible chemical knockout method. Compared with traditional gene-editing tools, it can avoid potential genetic compensation, misunderstandings caused by spontaneous mutations, or gene knockouts that lead to embryonic death. To study the role of estrogen receptor alpha (ERα) in the occurrence and progression of menopausal arthritis, we report a chemical knockout strategy in which stable peptide-based (PROTACs) against ERα to inhibit their function. This chemical knockdown strategy can effectively and quickly inhibit ERα protein in vivo and in vitro. In the rat menopausal arthritis model, this study showed that inhibiting estrogen function by degrading ERα can significantly interfere with cartilage matrix metabolism and cause menopausal arthritis by up-regulating matrix metalloproteinase (MMP-13). The results of this study indicate that ERα is a crucial estrogen receptor for maintaining cartilage metabolism. Inhibition of ERα function by PROTACs can promote the progression of osteoarthritis.

MP68-13 ESTROGEN RECEPTOR ALPHA PREVENTS BLADDER CANCER VIA INPP4B INHIBITED AKT PATHWAY IN VITRO AND IN VIVO

2015 ◽  
Vol 193 (4S) ◽  
Author(s):  
Chiuan-Ren Yeh ◽  
Iawen Hsu ◽  
Hiroshi Miyamoto ◽  
Xue-Ru Wu ◽  
Chawnshang Chang ◽  
...  
Keyword(s):  
Bladder Cancer ◽  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Akt Pathway ◽  
Receptor Alpha

Membrane and Nuclear Estrogen Receptor Alpha Actions: From Tissue Specificity to Medical Implications

2017 ◽  
Vol 97 (3) ◽  
pp. 1045-1087 ◽  
Author(s):  
Jean-Francois Arnal ◽  
Françoise Lenfant ◽  
Raphaël Metivier ◽  
Gilles Flouriot ◽  
Daniel Henrion ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Reproductive Tract ◽  
Vascular System ◽  
Physiological Role ◽  
Receptor Alpha ◽  
Nuclear Signaling ◽  
Nuclear Estrogen Receptor

Estrogen receptor alpha (ERα) has been recognized now for several decades as playing a key role in reproduction and exerting functions in numerous nonreproductive tissues. In this review, we attempt to summarize the in vitro studies that are the basis of our current understanding of the mechanisms of action of ERα as a nuclear receptor and the key roles played by its two activation functions (AFs) in its transcriptional activities. We then depict the consequences of the selective inactivation of these AFs in mouse models, focusing on the prominent roles played by ERα in the reproductive tract and in the vascular system. Evidence has accumulated over the two last decades that ERα is also associated with the plasma membrane and activates non-nuclear signaling from this site. These rapid/nongenomic/membrane-initiated steroid signals (MISS) have been characterized in a variety of cell lines, and in particular in endothelial cells. The development of selective pharmacological tools that specifically activate MISS and the generation of mice expressing an ERα protein impeded for membrane localization have begun to unravel the physiological role of MISS in vivo. Finally, we discuss novel perspectives for the design of tissue-selective ER modulators based on the integration of the physiological and pathophysiological roles of MISS actions of estrogens.

scholarly journals Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

2011 ◽  
Vol 1 (1) ◽  
pp. 5 ◽  
Author(s):  
Danielle Meijer ◽  
Hans Gelderblom ◽  
Marcel Karperien ◽  
Anne-Marie Cleton-Jansen ◽  
Pancras CW Hogendoorn ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Beneficial Effect ◽  
Estrogen Receptor Alpha ◽  
Estrogen Signaling ◽  
Receptor Alpha

scholarly journals CLPTM1L induces estrogen receptor β signaling-mediated radioresistance in non-small cell lung cancer cells

2020 ◽  
Vol 18 (1) ◽  
Author(s):  
Hang Li ◽  
Jun Che ◽  
Mian Jiang ◽  
Ming Cui ◽  
Guoxing Feng ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Estrogen Receptor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Target Genes ◽  
Small Cell ◽  
Small Cell Lung

Abstract Introduction Radioresistance is a major challenge in lung cancer radiotherapy, and new radiosensitizers are urgently needed. Estrogen receptor β (ERβ) is involved in the progression of non-small cell lung cancer (NSCLC), however, the role of ERβ in the response to radiotherapy in lung cancer remains elusive. In the present study, we investigated the mechanism underlying ERβ-mediated transcriptional activation and radioresistance of NSCLC cells. Methods Quantitative real-time PCR, western blot and immunohistochemistry were used to detect the expression of CLPTM1L, ERβ and other target genes. The mechanism of CLPTM1L in modulation of radiosensitivity was investigated by chromatin immunoprecipitation assay, luciferase reporter gene assay, immunofluorescence staining, confocal microscopy, coimmunoprecipitation and GST pull-down assays. The functional role of CLPTM1L was detected by function assays in vitro and in vivo. Results CLPTM1L expression was negatively correlated with the radiosensitivity of NSCLC cell lines, and irradiation upregulated CLPTM1L in radioresistant (A549) but not in radiosensitive (H460) NSCLC cells. Meanwhile, IR induced the translocation of CLPTM1L from the cytoplasm into the nucleus in NSCLC cells. Moreover, CLPTM1L induced radioresistance in NSCLC cells. iTRAQ-based analysis and cDNA microarray identified irradiation-related genes commonly targeted by CLPTM1L and ERβ, and CLPTM1L upregulated ERβ-induced genes CDC25A, c-Jun, and BCL2. Mechanistically, CLPTM1L coactivated ERβ by directly interacting with ERβ through the LXXLL NR (nuclear receptor)-binding motif. Functionally, ERβ silencing was sufficient to block CLPTM1L-enhanced radioresistance of NSCLC cells in vitro. CLPTM1L shRNA treatment in combination with irradiation significantly inhibited cancer cell growth in NSCLC xenograft tumors in vivo. Conclusions The present results indicate that CLPTM1L acts as a critical coactivator of ERβ to promote the transcription of its target genes and induce radioresistance of NSCLC cells, suggesting a new target for radiosensitization in NSCLC therapy.

scholarly journals A sex-specific role for androgens in angiogenesis

2010 ◽  
Vol 207 (2) ◽  
pp. 345-352 ◽  
Author(s):  
Daniel P. Sieveking ◽  
Patrick Lim ◽  
Renée W.Y. Chow ◽  
Louise L. Dunn ◽  
Shisan Bao ◽  
...  
Keyword(s):  
Serum Levels ◽  
Dependent Manner ◽  
Androgen Treatment ◽  
Androgen Exposure ◽  
Androgen Sensitivity ◽  
Males And Females ◽  
Or Gene

Mounting evidence suggests that in men, serum levels of testosterone are negatively correlated to cardiovascular and all-cause mortality. We studied the role of androgens in angiogenesis, a process critical in cardiovascular repair/regeneration, in males and females. Androgen exposure augmented key angiogenic events in vitro. Strikingly, this occurred in male but not female endothelial cells (ECs). Androgen receptor (AR) antagonism or gene knockdown abrogated these effects in male ECs. Overexpression of AR in female ECs conferred androgen sensitivity with respect to angiogenesis. In vivo, castration dramatically reduced neovascularization of Matrigel plugs. Androgen treatment fully reversed this effect in male mice but had no effect in female mice. Furthermore, orchidectomy impaired blood-flow recovery from hindlimb ischemia, a finding rescued by androgen treatment. Our findings suggest that endogenous androgens modulate angiogenesis in a sex-dependent manner, with implications for the role of androgen replacement in men.

scholarly journals The role of G-protein-coupled membrane estrogen receptor in mouse Leydig cell function—in vivo and in vitro evaluation

2018 ◽  
Vol 374 (2) ◽  
pp. 389-412 ◽  
Author(s):  
M. Kotula-Balak ◽  
P. Pawlicki ◽  
A. Milon ◽  
W. Tworzydlo ◽  
M. Sekula ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
G Protein ◽  
Leydig Cell ◽  
Cell Function ◽  
G Protein Coupled ◽  
Mouse Leydig Cell ◽  
Leydig Cell Function

scholarly journals A bi-faceted role of estrogen receptor β in breast cancer

2013 ◽  
Vol 20 (3) ◽  
pp. R127-R139 ◽  
Author(s):  
Etienne Leygue ◽  
Leigh C Murphy
Keyword(s):  
Breast Cancer ◽  
Estrogen Receptor ◽  
Large Body ◽  
Estrogen Receptor Β ◽  
Cancer Tissue ◽  
Culture Studies ◽  
Growth And Survival

Despite over 15 years of research, the exact role, if any, played by estrogen receptor β (ERβ) in human breast cancer remains elusive. A large body of data bothin vitroandin vivosupports its role as an antiproliferative, pro-apoptotic factor especially when co-expressed with ERα. However, there is a smaller body of data associating ERβ with growth and survival in breast cancer. In clinical studies and most often in cell culture studies, the pro-growth and pro-survival activity of ERβ occurs in ERα-negative breast cancer tissue and cells. This bi-faceted role of ERβ is discussed in this review.

scholarly journals Estrogen Receptor Alpha Expression in Podocytes Mediates Protection against Apoptosis In-Vitro and In-Vivo

PLoS ONE ◽  
2011 ◽  
Vol 6 (11) ◽  
pp. e27457 ◽  
Author(s):  
Sebastian Kummer ◽  
Stefanie Jeruschke ◽  
Lara Vanessa Wegerich ◽  
Andrea Peters ◽  
Petra Lehmann ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Estrogen Receptor Alpha ◽  
Receptor Alpha

scholarly journals The Role of Estriol and Estrone in Keratoconic Stromal Sex Hormone Receptors

2022 ◽  
Vol 23 (2) ◽  
pp. 916
Author(s):  
Paulina Escandon ◽  
Sarah E. Nicholas ◽  
Rebecca L. Cunningham ◽  
David A. Murphy ◽  
Kamran M. Riaz ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Stromal Cells ◽  
Estrogen Receptor Alpha ◽  
Hormone Receptors ◽  
Estrogen Receptor Beta ◽  
Corneal Stroma ◽  
Sex Hormone ◽  
Human Cornea

Keratoconus (KC) is a progressive corneal thinning disease that manifests in puberty and worsens during pregnancy. KC onset and progression are attributed to diverse factors that include: environmental, genetics, and hormonal imbalances; however, the pathobiology remains elusive. This study aims to determine the role of corneal stroma sex hormone receptors in KC and their interplay with estrone (E1) and estriol (E3) using our established 3D in vitro model. Healthy cornea stromal cells (HCFs) and KC cornea stromal cells (HKCs), both male and female, were stimulated with various concentrations of E1 and E3. Significant changes were observed between cell types, as well as between males and females in the sex hormone receptors tested; androgen receptor (AR), progesterone receptor (PR), estrogen receptor alpha (ERα), and estrogen receptor beta (ERβ) using Western blot analysis. E1 and E3 stimulations in HCF females showed AR, PR, and ERβ were significantly upregulated compared to HCF males. In contrast, ERα and ERβ had significantly higher expression in HKC’s females than HKC’s males. Our data suggest that the human cornea is a sex-dependent, hormone-responsive tissue that is significantly influenced by E1 and E3. Therefore, it is plausible that E1, E3, and sex hormone receptors are involved in the KC pathobiology, warranting further investigation.

scholarly journals 3,3′-Diindolylmethane Dose-Dependently Prevents Advanced Prostate Cancer

2019 ◽  
Author(s):  
Yufei Li ◽  
Nathaniel W. Mahloch ◽  
Nicholas J.E. Starkey ◽  
Mónica Peña-Luna ◽  
George E. Rottinghaus ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Estrogen Receptor ◽  
High Fat Diet ◽  
Estrogen Receptor Alpha ◽  
Estrogen Receptor Beta ◽  
Control Group ◽  
High Fat ◽  
Mouse Prostate

Abstract3,3′-Diindolylmethane (DIM) is an acid-derived dimer of indole-3-carbinol, found in many cruciferous vegetables, such as broccoli, and has been shown to inhibit prostate cancer (PCa) in several in vitro and in vivo models. We demonstrated that DIM stimulated both estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ) transcriptional activities and propose that ERβ plays a role in mediating DIM’s inhibition on cancer cell growth. To further study the effects of DIM on inhibiting advanced PCa development, we tested DIM in TRAMP (TRansgenic Adenocarcinoma of the Mouse Prostate) mice. The control group of mice were fed a high fat diet. Three additional groups of mice were fed the same high fat diet supplemented with 0.04%, 0.2% and 1% DIM. Incidence of advanced PCa, poorly differentiated carcinoma (PDC), in the control group was 60%. 1% DIM dramatically reduced PDC incidence to 24% (p=0.0012), while 0.2% and 0.04% DIM reduced PDC incidence to 38% (p=0.047) and 45% (p=0.14) respectively. Though DIM did affect mice weights, statistical analysis showed a clear negative association between DIM concentration and PDC incidence with p=0.004, while the association between body weight and PDC incidence was not significant (p=0.953). In conclusion, our results show that dietary DIM can inhibit the most aggressive stage of prostate cancer at concentration lower than previously demonstrated, possibly working through an estrogen receptor mediated mechanism.

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