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Suppression of estrogen receptor-beta promotes gastric cancer cell apoptosis with induction of autophagy.

ABSTRACT: Estrogen Receptor 2 (ESR2) is the protein-coding gene of estrogen receptor ? (ER?) and has been shown to be abundantly expressed in gastric carcinoma (GC), suggesting that it plays a role in GC pathogenesis. However, the underlying molecular mechanism remains elusive. In the present in vitro study, GC cell growth was found to be estrogen-dependent, and the expression level of ER? was higher than that of ER?. Knocking down the endogenous expression of ESR2 in GC cells increased the apoptosis rate and the level of cleaved caspase-3, caspase-7 and poly ADP-ribose polymerase. The induced apoptosis was primarily related to GC cell growth arrest, accompanied with activation of DNA damage-inducible protein 45 alpha (GADD45?) in a p53-independent manner. Importantly, down-regulation of ESR2 also promoted autophagy. The autophagy inhibitor 3-MA or silencing ATG7 rescued the apoptosis by knocking down ESR2 via activation of the MAPK signaling pathway in AGS cells, leading to increased apoptosis. In conclusion, these results demonstrated that suppression of ESR2 gene expression could promote GC cell apoptosis, suggesting that it may prove to be a potential therapeutic target for GC.

SUBMITTER: Zhou F

PROVIDER: S-EPMC7476128 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Suppression of estrogen receptor-beta promotes gastric cancer cell apoptosis with induction of autophagy.

Zhou Fan F Jin Jingjing J Zhou Lin L Wu Longyun L Cao Yu Y Yan Hongli H Huang Qin Q Wang Lei L Zou Xiaoping X

American journal of translational research 20200815 8

Estrogen Receptor 2 (ESR2) is the protein-coding gene of estrogen receptor β (ERβ) and has been shown to be abundantly expressed in gastric carcinoma (GC), suggesting that it plays a role in GC pathogenesis. However, the underlying molecular mechanism remains elusive. In the present <i>in vitro</i> study, GC cell growth was found to be estrogen-dependent, and the expression level of ERβ was higher than that of ERα. Knocking down the endogenous expression of ESR2 in GC cells increased the apoptos ...[more]

PMID: 32913514

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Project description:Recent researches have shown that estrogen receptor-β (ERβ) activator may be a potent anticancer agent for prostate cancer (PCa), and our previous study also indicated that dioscin can upregulate the expression of ERβ in MC3T3-E1 cell. In the present work, the activity and mechanism of dioscin, a natural product, against PCa were investigated. The results showed that dioscin markedly inhibited cell viability, colony formation, motility and induced apoptosis in PC3 cells. Moreover, dioscin disrupted the formation of PC3 cell-derived mammospheres and reduced aldehyde dehydrogenase (ALDH) level and the CD133+/CD44+ cells, indicating that dioscin had a potent inhibitory activity on prostate cancer stem cells (PCSCs). In vivo results also showed that dioscin significantly suppressed the tumor growth of PC3 cell xenografts in nude mice. Furthermore, mechanism investigation showed that dioscin markedly upregulated ERβ expression level, subsequently increased prolyl hydroxylase 2 level, decreased the levels of hypoxia-inducible factor-1α, vascular endothelial growth factor A and BMI-1, and thus induced cell apoptosis by regulating the expression levels of caspase-3 and Bcl-2 family proteins. In addition, transfection experiment of ERβ-siRNA further indicated that diosicn showed excellent activity against PCa in vitro and in vivo by increasing ERβ expression level. The co-immunoprecipitation (Co-IP) results further suggested that dioscin promoted the interaction of c-ABL and ERβ, but did not change c-ABL expression. Moreover, the molecular docking assay showed that dioscin processed powerful affinity toward to ERβ mainly through the strong hydrogen bonding and hydrophobic effects, and the actions of dioscin on ERβ activation and tumor cells inhibition were significantly weakened in the mutational (Phe-336, Phe-468) PC3 cells. Collectively, these findings proved that dioscin exerted efficient anti-PCa activity via activation of ERβ, which should be developed as an efficient candidate in clinical for treating this cancer in the future.

Project description:IntroductionOf the nearly 1.4 million new cases of breast cancer diagnosed each year, a large proportion is characterized as hormone receptor negative, lacking estrogen receptors (ER) and/or progesterone receptors (PR). Patients with receptor-negative tumors do not respond to current steroid hormone-based therapies and generally have significantly higher risk of recurrence and mortality compared with patients with tumors that are ER- and/or PR-positive. Previous in vitro studies had shown that the progesterone metabolites, 5α-dihydroprogesterone (5αP) and 3α-dihydroprogesterone (3αHP), respectively, exhibit procancer and anticancer effects on receptor-negative human breast cell lines. Here in vivo studies were conducted to investigate the ability of 5αP and 3αHP to control initiation, growth, and regression of ER/PR-negative human breast cell tumors.MethodsER/PR-negative human breast cells (MDA-MB-231) were implanted into mammary fat pads of immunosuppressed mice, and the effects of 5αP and 3αHP treatments on tumor initiation, growth, suppression/regression, and histopathology were assessed in five separate experiments. Specific radioimmunoassays and gas chromatography-mass spectrometry were used to measure 5αP, 3αHP, and progesterone in mouse serum and tumors.ResultsOnset and growth of ER/PR-negative human breast cell tumors were significantly stimulated by 5αP and inhibited by 3αHP. When both hormones were applied simultaneously, the stimulatory effects of 5αP were abrogated by the inhibitory effects of 3αHP and vice versa. Treatment with 3αHP subsequent to 5αP-induced tumor initiation resulted in suppression of further tumorigenesis and regression of existing tumors. The levels of 5αP in tumors, regardless of treatment, were about 10-fold higher than the levels of 3αHP, and the 5αP:3αHP ratios were about fivefold higher than in serum, indicating significant changes in endogenous synthesis of these hormones in tumorous breast tissues.ConclusionsThe studies showed that estrogen/progesterone-insensitive breast tumors are sensitive to, and controlled by, the progesterone metabolites 5αP and 3αHP. Tumorigenesis of ER/PR-negative breast cells is significantly enhanced by 5αP and suppressed by 3αHP, the outcome depending on the relative concentrations of these two hormones in the microenvironment in the breast regions. The findings show that the production of 5αP greatly exceeds that of 3αHP in ER/PR-negative tumors and that treatment with 3αHP can effectively block tumorigenesis and cause existing tumors to regress. The results provide the first hormonal theory to explain tumorigenesis of ER/PR-negative breast tissues and support the hypothesis that a high 3αHP-to-5αP concentration ratio in the microenvironment may foster normalcy in noncancerous breast regions. The findings suggest new diagnostics based on the relative levels of these hormones and new approaches to prevention and treatment of breast cancers based on regulating the levels and action mechanisms of anti- and pro-cancer progesterone metabolites.

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Suppression of estrogen receptor-beta promotes gastric cancer cell apoptosis with induction of autophagy.

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Suppression of estrogen receptor-beta promotes gastric cancer cell apoptosis with induction of autophagy.

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