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Estrogen receptor ? exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

ABSTRACT: Estrogen receptor ? (ER?) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ER?, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ER? is expressed in both basal and luminal cells in the prostate while AR is expressed in luminal but not in the basal cell layer which harbors the prostate stem cells. To investigate the mechanisms of action of ER? and its potential cross-talk with AR, we used RNA-seq to study the effects of estradiol or the synthetic ligand, LY3201, in AR-positive LNCaP PCa cells which had been engineered to express ER?. Transcriptomic analysis indicated relatively few changes in gene expression with ER? overexpression, but robust responses following ligand treatments. There is significant overlap of responsive genes between the two ligands, estradiol and LY3201 as well as ligand-specific alterations. Gene set analysis of down-regulated genes identified an enrichment of androgen-responsive genes, such as FKBP5, CAMKK2, and TBC1D4. Consistently, AR transcript, protein levels, and transcriptional activity were down-regulated following ER? activation. In agreement with this, we find that the phosphorylation of the CAMKK2 target, AMPK, was repressed by ligand-activated ER?. These findings suggest that ER?-mediated signaling pathways are involved in the negative regulation of AR expression and activity, thus supporting a tumor suppressive role for ER? in PCa.

SUBMITTER: Chaurasiya S

PROVIDER: S-EPMC7228066 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

Chaurasiya Surendra S Widmann Scott S Botero Cindy C Lin Chin-Yo CY Gustafsson Jan-Åke JÅ Strom Anders M AM

PloS one 20200515 5

Estrogen receptor β (ERβ) was first identified in the rodent prostate and is abundantly expressed in human and rodent prostate epithelium, stroma, immune cells and endothelium of the blood vessels. In the prostates of mice with inactivated ERβ, mutant phenotypes include epithelial hyperplasia and increased expression of androgen receptor (AR)-regulated genes, most of which are also upregulated in prostate cancer (PCa). ERβ is expressed in both basal and luminal cells in the prostate while AR is ...[more]

PMID: 32413024

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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.

Dataset Information

Estrogen receptor ? exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

Publications

Estrogen receptor β exerts tumor suppressive effects in prostate cancer through repression of androgen receptor activity.

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