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Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor ? by XCT790 and siRNA.

ABSTRACT: Purpose:To explore the targeted therapy of estrogen-related receptor ? (ERR?) in endometrial cancer (EC) cells and its potential mechanisms. Methods:The mRNA and protein expression levels of ERR? and estrogen receptor ? (ER?) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERR?-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERR? (siRNA-ERR?), cell proliferation and apoptosis were evaluated by MTS assay and flow cytometry. After treatment with siRNA-ERR?, the expression profiles of transcription factors (TFs) were analyzed by protein/DNA arrays in EC cells. Results:The relative mRNA levels of ERRa in RL-952 (1±0.0831) and AN3-CA (1.162±0.0325) were significantly higher than those in HEC-1A (0.3081±0.0339) and HEC-1B (0.1119±0.0091) (P<0.05), and similar results were observed for ERR? protein levels. A higher ratio of ERa/ERRa was observed in ER?-positive RL-952 (10-fold) and ANC-3A (8.5-fold) cells, whereas a lower ratio was observed in ER?-negative HEC-1A (3.75-fold) and HEC-1B cells (0-fold). Both - exogenous XCT790 and endogenous siRNA-ERR? - can decrease the expression of ERR?, thereby inhibiting proliferation but promoting apoptosis in both ER?-positive and -negative EC cells. The XCT790 presented higher proliferation-inhibition and apoptosis rates in the ER?-positive than ER?-negative cells, whereas the siRNA-ERR? exhibited higher proliferation-inhibition and apoptosis rates in the ER?-negative than in ER?-positive cells. In total, 3 upregulated and 17 downregulated TFs were screened out by knocked-down expression of ERR? in all EC cells. Among them, the upregulated TFs organic cation transporter 3/4(Oct3/4), hepatic nuclear factor 4 (HNF4), HNF4 and chicken ovalbumin upstream TF (COUP-TF) as well as downregulated transcription factor EB (TFEB) were found to be statistically significant (P<0.05). Conclusion:Targeting ERR? provides a promising novel endocrine therapeutic strategy.

SUBMITTER: Sun P

PROVIDER: S-EPMC6089116 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA.

Sun PengMing P Mao XiaoDan X Gao Min M Huang MeiMei M Chen LiLi L Ruan GuanYu G Huang WeiYi W Braicu Elena Ioana EI Sehouli Jalid J

Cancer management and research 20180810

<h4>Purpose</h4>To explore the targeted therapy of estrogen-related receptor α (ERRα) in endometrial cancer (EC) cells and its potential mechanisms.<h4>Methods</h4>The mRNA and protein expression levels of ERRα and estrogen receptor α (ERα) were detected by qPCR and Western blotting in RL-952, AN3-CA, HEC-1A, and HEC-1B EC cell lines. After treatment with the ERRα-specific antagonist XCT790 or infection with lentivirus-mediated small interfering RNA (siRNA) targeting the ERRα (siRNA-ERRα), cell ...[more]

PMID: 30127640

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Project description:BackgroundONC201 is a dopamine receptor D2 (DRD2) antagonist that inhibits tumor growth in preclinical models through ClpP activation to induce integrated stress response pathway and mitochondrial events related to inhibition of cell growth, which is being explored in clinical trials for solid tumors and hematological malignancies. In this study, we investigated the anti-tumorigenic effect of ONC201 in endometrial cancer cell lines and a genetically engineered mouse model of endometrial cancer.MethodsCell proliferation was assessed by MTT and colony formation assays. Cell cycle and apoptosis were evaluated by Cellometer. Invasion capacity was tested using adhesion, transwell and wound healing assays. LKB1fl/flp53fl/fl mouse model of endometrial cancer were fed a control low fat diet versus a high fat diet to mimic diet-induced obesity. Following tumor onset, mice were treated with placebo or ONC201. Metabolomics and lipidomics were used to identify the obesity-dependent effects of ONC201 in the mouse endometrial tumors. DRD2 expression was analyzed by immunohistochemistry in human endometrioid and serous carcinoma specimens. DRD2 mRNA expression from the Cancer Genome Atlas (TCGA) database was compared between the four molecular subtypes of endometrial cancer.ResultsIncreasing DRD2 expression in endometrial cancer was significantly associated with grade, serous histology and stage, as well as worse progression free survival and overall survival. Higher expression of DRD2 mRNA was found for the Copy Number High (CNH) subtype when compared to the other subtypes. ONC201 inhibited cell proliferation, induced cell cycle G1 arrest, caused cellular stress and apoptosis and reduced invasion in endometrial cancer cells. Diet-induced obesity promoted endometrial tumor growth while ONC201 exhibited anti-tumorigenic efficacy in the obese and lean LKB1fl/fl/p53fl/fl mice. Metabolomic analysis demonstrated that ONC201 reversed the obesity-driven upregulation of lipid biosynthesis and reduced protein biosynthesis in obese and lean mice.ConclusionONC201 has anti-tumorigenic effects in endometrial cancer cells and a transgenic mouse model of endometrial cancer, and DRD2 expression was documented in both human serous and endometrioid endometrial cancer. These studies support DRD2 antagonism via ONC201 as a promising therapeutic strategy for endometrial cancer that has already demonstrated pharmacodynamic activity and clinical benefit in both serous and endometrioid endometrial cancer patients.

Dataset Information

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor ? by XCT790 and siRNA.

Publications

Novel endocrine therapeutic strategy in endometrial carcinoma targeting estrogen-related receptor α by XCT790 and siRNA.

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