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Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist.

ABSTRACT: Ovarian cancer (OCa) is the deadliest gynecologic cancer. Emerging studies suggest ovarian cancer stem cells (OCSCs) contribute to chemotherapy resistance and tumor relapse. Recent studies demonstrated estrogen receptor beta (ERβ) exerts tumor suppressor functions in OCa. However, the status of ERβ expression in OCSCs and the therapeutic utility of the ERβ agonist LY500307 for targeting OCSCs remain unknown. OCSCs were enriched from ES2, OV90, SKOV3, OVSAHO, and A2780 cells using ALDEFLUOR kit. RT-qPCR results showed ERβ, particularly ERβ isoform 1, is highly expressed in OCSCs and that ERβ agonist LY500307 significantly reduced the viability of OCSCs. Treatment of OCSCs with LY500307 significantly reduced sphere formation, self-renewal, and invasion, while also promoting apoptosis and G2/M cell cycle arrest. Mechanistic studies using RNA-seq analysis demonstrated that LY500307 treatment resulted in modulation of pathways related to cell cycle and apoptosis. Western blot and RT-qPCR assays demonstrated the upregulation of apoptosis and cell cycle arrest genes such as FDXR, p21/CDKN1A, cleaved PARP, and caspase 3, and the downregulation of stemness markers SOX2, Oct4, and Nanog. Importantly, treatment of LY500307 significantly attenuated the tumor-initiating capacity of OCSCs in orthotopic OCa murine xenograft models. Our results demonstrate that ERβ agonist LY500307 is highly efficacious in reducing the stemness and promoting apoptosis of OCSCs and shows significant promise as a novel therapeutic agent in treating OCa.

SUBMITTER: He Y

PROVIDER: S-EPMC9266546 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist

Project description:We examined the transcriptional changes altered by ERβ agonist LY500307 treatment in ovarian cancer stem cells (OCSCs) by performing global transcriptome analysis. SKOV3-ALDH+ OCSCs were treated with vehicle or LY500307 (5 µM) for 24 h and the RNA was isolated and utilized for RNA-seq analysis. Our results demonstrated that the top pathways altered by LY500307 were related to cell cycle and apoptosis. Functional enrichment using GSEA analysis showed that LY500307-regulated genes showed positive enrichment in the p53 pathway, oxidative phosphorylation, apoptosis and estrogen late response genes, and negative correlation with E2F targets, G2/M checkpoint and mitotic spindle.

2022-07-13 | GSE197320 | GEO

Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist

Project description:Therapeutic Targeting of Ovarian Cancer Stem Cells Using Estrogen Receptor Beta Agonist

| PRJNA809731 | ENA

A Novel Estrogen Receptor β Agonist Diminishes Ovarian Cancer Stem Cells via Suppressing the Epithelial-to-Mesenchymal Transition.

Project description:Epithelial ovarian cancer is the most lethal malignancy of the female reproductive tract. A healthy ovary expresses both Estrogen Receptor α (ERα) and β (ERβ). Given that ERα is generally considered to promote cell survival and proliferation, thereby, enhancing tumor growth, while ERβ shows a protective effect against the development and progression of tumors, the activation of ERβ by its agonists could be therapeutically beneficial for ovarian cancer. Here, we demonstrate that the activation of ERβ using a newly developed ERβ agonist, OSU-ERb-12, can impede ovarian cancer cell expansion and tumor growth in an ERα-independent manner. More interestingly, we found that OSU-ERb-12 also reduces the cancer stem cell (CSC) population in ovarian cancer by compromising non-CSC-to-CSC conversion. Mechanistically, we revealed that OSU-ERb-12 decreased the expression of Snail, a master regulator of the epithelial-to-mesenchymal transition (EMT), which is associated with de novo CSC generation. Given that ERα can mediate EMT and facilitate maintenance of the CSC subpopulation and that OSU-ERb-12 can block the transactivity of ERα, we conclude that OSU-ERb-12 reduces the CSC subpopulation by inhibiting EMT in an ERα-dependent manner. Taken together, our data indicate that the ERβ agonist OSU-ERb-12 could be used to hinder tumor progression and limit the CSC subpopulation with the potential to prevent tumor relapse and metastasis in patients with ovarian cancer.

| S-EPMC9105687 | biostudies-literature

Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer.

Project description:Ovarian cancer is the deadliest of all gynecologic cancers. Despite success with initial chemotherapy, the majority of patients relapse with an incurable disease. Development of chemotherapy resistance is a major factor for poor long-term survival in ovarian cancer. The biological effects of estrogens are mediated by estrogen receptor alpha (ERα) and estrogen receptor beta (ERβ). Emerging evidence suggests that ovarian cancer cells express ERβ that functions as a tumor suppressor; however, the clinical utility of ERβ agonists in ovarian cancer remains elusive. We tested the utility of two natural ERβ agonists liquiritigenin (Liq), which is isolated from Glycyrrhiza uralensis and S-equol, which is isolated from soy isoflavone daidzein, for treating ovarian cancer. Both natural ERβ ligands had significant growth inhibition in cell viability and survival assays, reduced migration and invasion, and promoted apoptosis. Further, ERβ agonists showed tumor suppressive functions in therapy-resistant ovarian cancer model cells and sensitized ovarian cancer cells to cisplatin and paclitaxel treatment. Global RNA-Seq analysis revealed that ERβ agonists modulate several tumor suppressive pathways, including downregulation of the NF-κB pathway. Immunoprecipitation assays revealed that ERβ interacts with p65 subunit of NF-κB and ERβ overexpression reduced the expression of NF-κB target genes. In xenograft assays, ERβ agonists reduced tumor growth and promoted apoptosis. Collectively, our findings demonstrated that natural ERβ agonists have the potential to significantly inhibit ovarian cancer cell growth by anti-inflammatory and pro-apoptotic actions, and natural ERβ agonists represent novel therapeutic agents for the management of ovarian cancer.

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Therapeutic utility of natural estrogen receptor beta agonists on ovarian cancer

Project description:We examined the transcriptional changes modulated by ESR2 agonist liquiritigenin by perfroming global transcriptome analysis. ES2 cells were treated with either vehicle or liquiritigenin for 24 h and the isolated RNA was utilized for RNA-seq analysis. Our results demonstrated that liquiritigenin modulated several genes that are involved in NF-kB signaling, inflammation, NRF2 mediated oxidative stress response, and MMP signaling.

2017-09-18 | GSE93807 | GEO

Targeting estrogen-related receptor alpha inhibits epithelial-to-mesenchymal transition and stem cell properties of ovarian cancer cells.

Project description:Epithelial-mesenchymal transition represents a key event in cancer progression and has emerged as a promising anticancer target. Estrogen-related receptor alpha (ERRα) is frequently elevated in advanced-stage ovarian cancer, but its potential role in tumor progression is not known. Here we show that ERRα functions in epithelial-mesenchymal transition and in subsequent stem cell traits responsible for the acquisition of high degree of aggressiveness and potential for metastasis that are characteristic of ovarian cancer. Importantly, targeted inhibition of ERRα also inhibited the expression of Snail, a repressor of E-cadherin and an inducer of epithelial-mesenchymal transition. Interestingly, induction of Snail resulted from not only changes in mRNA transcription rate but also mRNA stability. We thus identified the miR-200 family as a new player in the ERRα-mediated posttranscriptional regulation of Snail, and antagonism of miR-200a/b could revert the decreased expression of Snail and reversal of epithelial-mesenchymal transition and stem cell characteristics due to ERRα depletion. Finally, we showed that RNA interference-mediated inhibition of ERRα significantly reduced tumor burden, ascites formation, and metastatic peritoneal nodules in vivo in an orthotopic model of ovarian cancer. These results suggest ERRα activation as a mechanism of tumor aggressiveness and imply that targeting ERRα may be a promising approach in ovarian cancer treatment.

| S-EPMC3982489 | biostudies-literature

Estrogen Receptor ? as a Therapeutic Target in Breast Cancer Stem Cells.

Project description:BackgroundBreast cancer cells with tumor-initiating capabilities (BSCs) are considered to maintain tumor growth and govern metastasis. Hence, targeting BSCs will be crucial to achieve successful treatment of breast cancer.MethodsWe characterized mammospheres derived from more than 40 cancer patients and two breast cancer cell lines for the expression of estrogen receptors (ERs) and stem cell markers. Mammosphere formation and proliferation assays were performed on cells from 19 cancer patients and five healthy individuals after incubation with ER-subtype selective ligands. Transcriptional analysis was performed to identify pathways activated in ER?-stimulated mammospheres and verified using in vitro experiments. Xenograft models (n?=?4 or 5 per group) were used to study the role of ERs during tumorigenesis.ResultsWe identified an absence of ER? but upregulation of ER? in BSCs associated with phenotypic stem cell markers and responsible for the proliferative role of estrogens. Knockdown of ER? caused a reduction of mammosphere formation in cell lines and in patient-derived cancer cells (40.7%, 26.8%, and 39.1%, respectively). Gene set enrichment analysis identified glycolysis-related pathways (false discovery rate < 0.001) upregulated in ER?-activated mammospheres. We observed that tamoxifen or fulvestrant alone was insufficient to block proliferation of patient-derived BSCs while this could be accomplished by a selective inhibitor of ER? (PHTPP; 53.7% in luminal and 45.5% in triple-negative breast cancers). Furthermore, PHTPP reduced tumor initiation in two patient-derived xenografts (75.9% and 59.1% reduction in tumor volume, respectively) and potentiated tamoxifen-mediated inhibition of tumor growth in MCF7 xenografts.ConclusionWe identify ER? as a mediator of estrogen action in BSCs and a novel target for endocrine therapy.

| S-EPMC5441302 | biostudies-literature

Epigenetic modifications of the Estrogen receptor beta gene in epithelial ovarian cancer cells.

Project description:The mechanisms of estrogen insensitivity or estrogen resistance in ovarian cancer cells are not known. Studies on regulation of the estrogen receptor (ER) gene have suggested a role for epigenetics in silencing ER expression.Cells from insensitive ovarian cancer cells, SKOV3 and HEY, were cultured with and without the DNA methyltransferase (DNMT) inhibitor, 5-aza-2'-deoxycytidine (AzaC) and the histone deacetylase (HDAC) inhibitor, trichostatin (TSA). ERbeta promoter methylation was examined using bisulfite sequencing. RNA was collected for oligonucleotide array studies.Cell type-specific ERbeta promoter methylation was found as well as relative hypomethylation of the ERbeta promoter in SKOV3 compared to HEY cells. Preferential demethylation of specific CpGs by different treatments was found. AzaC and TSA resulted in significant tumor growth inhibition and alterations in expression of numerous genes.The ERbeta promoter is differentially methylated in ovarian cancer cells. Moreover, AzaC and TSA can inhibit ovarian cancer cell growth.

| S-EPMC2737468 | biostudies-literature

Agonist activation of estrogen receptor beta (ER?) sensitizes malignant pleural mesothelioma cells to cisplatin cytotoxicity.

Project description:BackgroundEstrogen receptor (ER) ? acts as a tumor suppressor in malignant mesotheliomas.MethodsHere we explored the anti-proliferative and anti-tumorigenic efficacy of the selective ER? agonist, KB9520, in human mesothelioma cell lines in vitro and in a mesothelioma mouse model in vivo.ResultsKB9520 showed significant anti-proliferative effect in ER? positive human malignant pleural mesothelioma cells in vitro. Selective activation of ER? with KB9520 sensitized the cells to treatment with cisplatin, resulting in enhanced growth inhibition and increased apoptosis. Furthermore, in CD1 nude mice mesothelioma tumor growth was significantly inhibited when KB9520 was added on top of the standard of care chemo combination cisplatin/pemetrexed, as compared to the cisplatin/pemetrexed alone group. Importantly, KB9520 exerted a protective effect to cisplatin toxicity in the non-malignant mesothelium derived MET5A cells.ConclusionsTogether, the data presented suggest that selective targeting of ER? may be an efficacious stand-alone treatment option and/or become an important add-on to existing malignant mesothelioma therapy.

| S-EPMC4197308 | biostudies-literature

Liquiritigenin is a plant-derived highly selective estrogen receptor beta agonist.

Project description:After the Women's Health Initiative found that the risks of hormone therapy outweighed the benefits, a need for alternative drugs to treat menopausal symptoms has emerged. We explored the possibility that botanical agents used in Traditional Chinese Medicine for menopausal symptoms contain ERbeta-selective estrogens. We previously reported that an extract containing 22 herbs, MF101 has ERbeta-selective properties. In this study we isolated liquiritigenin, the most active estrogenic compound from the root of Glycyrrhizae uralensis Fisch, which is one of the plants found in MF101. Liquiritigenin activated multiple ER regulatory elements and native target genes with ERbeta but not ERalpha. The ERbeta-selectivity of liquiritigenin was due to the selective recruitment of the coactivator steroid receptor coactivator-2 to target genes. In a mouse xenograph model, liquiritigenin did not stimulate uterine size or tumorigenesis of MCF-7 breast cancer cells. Our results demonstrate that some plants contain highly selective estrogens for ERbeta.

| S-EPMC2277338 | biostudies-literature

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