Inhibitory mechanisms of the transcriptional activity of androgen receptor by resveratrol: Implication of DNA binding and acetylation of the receptor

Harada, Naoki; Atarashi, Kiyotaka; Murata, Yohei; Yamaji, Ryoichi; Nakano, Yoshihisa; Inui, Hiroshi

doi:10.1016/j.jsbmb.2010.11.002

Cited by 23 publications

(27 citation statements)

References 31 publications

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“…Moreover, RSV has repeatedly been shown to down-regulate AR-signalling in PC cells [14], [16], [17], [24]. The following experiments were performed to demonstrate the ability of the synthetic fluorinated RSV-analog (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline (FIDAS-3, termed thereafter FIDAS) [19] to modulate AR-signalling in the PC cell lines (Table 2).…”

Section: Resultsmentioning

confidence: 99%

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Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

et al. 2014

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BackgroundAdvanced castration resistant prostate cancer (CRPC) is often characterized by an increase of C-terminally truncated, constitutively active androgen receptor (AR) variants. Due to the absence of a ligand binding domain located in the AR-C-terminus, these receptor variants (also termed ARΔLBD) are unable to respond to all classical forms of endocrine treatments like surgical/chemical castration and/or application of anti-androgens.MethodologyIn this study we tested the effects of the naturally occurring stilbene resveratrol (RSV) and (E)-4-(2, 6-Difluorostyryl)-N, N-dimethylaniline, a fluorinated dialkylaminostilbene (FIDAS) on AR- and ARΔLBD in prostate cancer cells. The ability of the compounds to modulate transcriptional activity of AR and the ARΔLBD-variant Q640X was shown by reporter gene assays. Expression of endogenous AR and ARΔLBD mRNA and protein levels were determined by qRT-PCR and Western Blot. Nuclear translocation of AR-molecules was analyzed by fluorescence microscopy. AR and ARΔLBD/Q640X homo-/heterodimer formation was assessed by mammalian two hybrid assays. Biological activity of both compounds in vivo was demonstrated using a chick chorioallantoic membrane xenograft assay.ResultsThe stilbenes RSV and FIDAS were able to significantly diminish AR and Q640X-signalling. Successful inhibition of the Q640X suggests that RSV and FIDAS are not interfering with the AR-ligand binding domain like all currently available anti-hormonal drugs. Repression of AR and Q640X-signalling by RSV and FIDAS in prostate cancer cells was caused by an inhibition of the AR and/or Q640X-dimerization. Although systemic bioavailability of both stilbenes is very low, both compounds were also able to downregulate tumor growth and AR-signalling in vivo.ConclusionRSV and FIDAS are able to inhibit the dimerization of AR and ARΔLBD molecules suggesting that stilbenes might serve as lead compounds for a novel generation of AR-inhibitors.

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Section: Resultsmentioning

confidence: 99%

“…Previous studies analyzing the effects of RSV on the nuclear translocation of AR remained controversial [16], [17]. In order to test the effects of RSV and FIDAS on the nuclear import of AR and ARΔLBD we transfected AR-negative PC-3 cells with EosFP-tagged AR or EGFP-tagged Q640X.…”

Section: Resultsmentioning

confidence: 99%

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

et al. 2014

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“…AR-Ac has been shown to be inhibited by Rosa rugosa Thunb. (Rosaceae) extracts , Resveratrol (a polyphenolic phytoalexin; Harada et al 2011), procyanidin B3 (Choi et al 2011, green tea catechins (Lee et al 2012) and allspice (Lee et al 2007), all of which result in a decrease in cancer cell proliferation but not all by the same mechanism, as detailed in Table 2. Furthermore, many HAT inhibitors have been described recently, which are targeted against specific enzymes such as p300 (curcumin) and Tip60 (NU9056, K Coffey & C N Robson 2012, unpublished data).…”

Section: Introductionmentioning

confidence: 99%

Regulation of the androgen receptor by post-translational modifications

Coffey

Robson

2012

Journal of Endocrinology

121

100

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The androgen receptor (AR) is a key molecule in prostate cancer and Kennedy's disease. Understanding the regulatory mechanisms of this steroid receptor is important in the development of potential therapies for these diseases. One layer of AR regulation is provided by post-translational modifications including phosphorylation, acetylation, sumoylation, ubiquitination and methylation. While these modifications have mostly been studied as individual events, it is becoming clear that these modifications can functionally interact with each other in a signalling pathway. In this review, the effects of all modifications are described with a focus on interplay between them and the functional consequences for the AR.

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“…Also the inhibitory effect of resveratrol on DHT-induced AR transcriptional activity in LNCaP-FGC cells is in good agreement with the previous studies reporting the suppression of AR expression and activity by this compound in PC3 and DU145 prostate cancer cells (Kai and Levenson, 2011). Harada et al demonstrated that resveratrol inhibited AR binding to PSA promoter by decreasing the acetylation and nuclear translocation of AR (Harada et al, 2011). Kotha et al have reported that resveratrol inhibited STAT3 activation in DU145 prostate cancer cells.…”

Section: Discussionmentioning

confidence: 99%

Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

Lee¹,

Kundu²,

Keum³

et al. 2014

Biomol Ther

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This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. www.biomolther.orgProstate cancer is the most frequently diagnosed cancer. Although prostate tumors respond to androgen ablation therapy at an early stage, they often acquire the potential of androgen-independent growth. Elevated transcriptional activity of androgen receptor (AR) and/or signal transducer and activator of transcription-3 (STAT3) contributes to the proliferation of prostate cancer cells. In the present study, we examined the effect of resveratrol, a phytoalexin present in grapes, on the reporter gene activity of AR and STAT3 in human prostate cancer (LNCaP-FGC) cells stimulated with interleukin-6 (IL-6) and/or dihydrotestosterone (DHT). Our study revealed that resveratrol suppressed the growth of LNCaP-FGC cells in a time-and concentration-dependent manner. Whereas the AR transcriptional activity was induced by treatment with either IL-6 or DHT, the STAT3 transcriptional activity was induced only by treatment with IL-6 but not with DHT. Resveratrol significantly attenuated IL-6-induced STAT3 transcriptional activity, and DHT-or IL-6-induced AR transcriptional activity. Treatment of cells with DHT plus IL-6 significantly increased the AR transcriptional activity as compared to DHT or IL-6 treatment alone and resveratrol markedly diminished DHT plus IL-6-induced AR transcriptional activity. Furthermore, the production of prostate-specific antigen (PSA) was decreased by resveratrol in the DHT-, IL-6-or DHT plus IL-6-treated LNCaP-FGC cells. Taken together, the inhibitory effects of resveratrol on IL-6-and/or DHTinduced AR transcriptional activity in LNCaP prostate cancer cells are partly mediated through the suppression of STAT3 reporter gene activity, suggesting that resveratrol may be a promising therapeutic choice for the treatment of prostate cancer.

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Inhibitory mechanisms of the transcriptional activity of androgen receptor by resveratrol: Implication of DNA binding and acetylation of the receptor

Cited by 23 publications

References 31 publications

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

Stilbene Induced Inhibition of Androgen Receptor Dimerization: Implications for AR and ARΔLBD-Signalling in Human Prostate Cancer Cells

Regulation of the androgen receptor by post-translational modifications

Resveratrol Inhibits IL-6-Induced Transcriptional Activity of AR and STAT3 in Human Prostate Cancer LNCaP-FGC Cells

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