Corepressive function of nuclear receptor coactivator 2 in androgen receptor of prostate cancer cells treated with antiandrogenReport as inadecuate




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BMC Cancer

, 16:332

Experimental therapeutics and drug development

Abstract

BackgroundRecruitment of cofactors in the interaction of the androgen receptor AR and AR ligands plays a critical role in determining androgenic-antiandrogenic effects of the AR ligand on signaling, but the functions of key cofactors, including nuclear receptor coactivator NCOA, remain poorly understood in prostate cancer cells treated with AR ligands.

MethodsWe examined prostate cancer cell lines LNCaP and VCaP expressing mutated and wild-type ARs, respectively, to clarify the significance of NCOAs in the effect of antiandrogens. Hydroxyflutamide showed antagonistic activity against VCaP and an agonistic effect on LNCaP. Bicalutamide served as an antagonist for both. We analyzed mRNA transcription and protein expression of NCOAs in these cells pretreated with dihydrotestosterone and thereafter treated with the mentioned antiandrogens. Transcriptional silencing of candidate NCOAs and AR was performed using small interfering RNA siRNA. Cell proliferation was evaluated with MTT assay.

ResultsLNCaP treated with bicalutamide showed an about four-fold increase in the expression of NCOA2 mRNA compared to those pretreated with dihydrotestosterone alone P <0.01. In VCaP pretreated with dihydrotestosterone, transcriptions of NCOA2 and NCOA7 were slightly increased with bicalutamide 1.96- and 2.42-fold, respectively and hydroxyflutamide 1.33-fold in both. With Western blotting, the expression of NCOA2 protein also increased in LNCaP cells treated with bicalutamide compared with that in control cells pretreated with dihydrotestosterone alone. Following silencing with siRNA for NCOA2, PSA levels in media with LNCaP receiving bicalutamide were elevated compared with those in non-silencing controls 101.6 ± 4.2 vs. 87.8 ± 1.4 ng-mL, respectively, P =0.0495. In LNCaP cells treated with dihydrotestosterone and bicalutamide, NCOA2-silencing was associated with a higher proliferation activity compared with non-silencing control and AR-silencing.

ConclusionNCOA2, which has been thought to be recruited as a coactivator, possibly plays a corepressive role in AR of prostate cancer cells when treated with antiandrogens, suggesting its potential as a therapeutic target.

KeywordsAndrogen receptor Antiandrogen Coactivator Corepressor Electronic supplementary materialThe online version of this article doi:10.1186-s12885-016-2378-y contains supplementary material, which is available to authorized users.

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Author: Keisuke Takeda - Noboru Hara - Tsutomu Nishiyama - Masayuki Tasaki - Fumio Ishizaki - Yoshihiko Tomita

Source: https://link.springer.com/







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