AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells

Streicher, Wolfgang; Zengerling, Friedemann; Laschak, Martin; Weidemann, Wolfgang; Höpfner, Michael; Schrader, Andres Jan; Jentzmik, Florian; Schrader, Mark; Cronauer, Marcus V.

doi:10.1007/s00345-012-0842-0

Cited by 20 publications

(24 citation statements)

References 24 publications

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“…Although RSV showed a tendency do down regulate Q640X-dimerization, inhibition of Q640X/Q640X-homodimer formation was only significantly affected by FIDAS (%Q640X-dimerization in stilbene untreated cells 100%, %Q640X-dimerization at 100 µM RSV 80%; %Q640X- dimerization at 50 µM FIDAS 50%) (Figure 5). Most interestingly RSV and FIDAS were able to significantly decrease AR/Q640X heterodimerization, recently observed to occur in the absence of androgens [30]. Heterodimerization was inhibited at RSV and FIDAS concentrations of 100 µM and 50 µM, respectively.…”

Section: Resultsmentioning

confidence: 69%

“…In the absence of androgens, co-expression of a full length AR with an ARΔLBD like Q640X or AR v567es was shown to form transcriptionally active heterodimers [30], [31]. As seen in Figure 3 Q640X did only weakly activate the PSA promoter driven reporter plasmid Q640X (4-fold basal activity of DHT-untreated AR which was set at 1).…”

Section: Resultsmentioning

confidence: 91%

“…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. Nuclear localization of the green fluorescent fusion proteins was subsequently analyzed by fluorescence microscopy [30]. As depicted in Figure 4 nuclear translocation AR or Q640X was not significantly affected by RSV.…”

Section: Resultsmentioning

confidence: 99%

“…The observation that RSV and FIDAS were able to inhibit signalling induced by AR/AR and Q640X/Q640X–homodimers (Figure 2) as well as by AR/Q640X-heterodimers (Figure 3) prompted us to analyze the effects of both compounds on the dimerization of AR and/or Q640X using a specially designed M2H Assay [30].…”

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: 69%

Section: Resultsmentioning

confidence: 91%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 2 more Smart Citations

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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“…In a preliminary study, the team of Stope et al [10] provides Wrst experimental evidence that the small heat shock protein HSP27 is not only involved in folding and stability of client proteins but has also an impact on the regulation of messenger RNA in PCa cells. Finally, Streicher et al [11] present an experimental model system designed to select next-generation AR-antagonists targeting the N-terminus of the AR as described by Sadar in this issue.…”

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confidence: 99%

Molecular aspects of prostate cancer

Cronauer

Čulig

2012

World J Urol

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Androgen receptor aberrations in the era of abiraterone and enzalutamide

et al. 2015

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Prostate cancer is the most prevalent non-skin cancer and the second leading cause of cancer death in men of the western world. As growth and differentiation of prostate cancer largely depend on androgens, inhibition of the androgen/androgen receptor signaling axis is the main treatment for locally advanced and/or metastatic tumors. Although first-line androgen deprivation therapies like chemical/surgical castration and/or administration of anti-androgens are able to control the disease for several years, prostate cancer almost invariably recurs as castration-resistant prostate cancer. This stage of the disease is characterized by a sustained AR-signaling despite castrate levels of circulating androgens. Various molecular mechanisms were shown to induce castration resistance. This review will discuss the most recent and relevant experimental findings on AR-signaling in castration-resistant prostate cancer in order to provide a comprehensive interpretation of the clinical behavior of this tumor entity following treatments with abiraterone, enzalutamide, ARN-509 or taxanes.

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AR-Q640X, a model to study the effects of constitutively active C-terminally truncated AR variants in prostate cancer cells

Cited by 20 publications

References 24 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

Molecular aspects of prostate cancer

Androgen receptor aberrations in the era of abiraterone and enzalutamide

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