Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines

Laschak, Martin; Bechtel, Marina; Spindler, Klaus-Dieter; Hessenauer, Andrea

doi:10.3892/ijmm.2011.735

Cited by 13 publications

(16 citation statements)

References 22 publications

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“…Our data indicate that this effect can be prevented by the presence of nuclear FlnA but further studies are needed to elucidate the mechanism by which FlnA promotes this effect. In this respect, FlnA is distinct from other AR co-repressors such as NCoR and SMRT and likely explains results showing the inability of the latter to inhibit AR activity in CRPC lines (Laschak, et al 2011). …”

Section: Discussionmentioning

confidence: 99%

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

Mooso¹,

Vinall²,

Tepper³

et al. 2012

Endocrine-Related Cancer

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Since prostate cancer (CaP) is regulated by androgen receptor (AR) activity, metastatic CaP is treated with androgen deprivation therapy (ADT). Despite initial response, patients on ADT eventually progress to castration-resistant CaP (CRPC), which is currently incurable. We previously showed that cleavage of the 280kDa structural protein Filamin A (FlnA) to a 90kDa fragment, and nuclear localization of the cleaved product, sensitized CRPC cells to ADT. Hence, treatment promoting FlnA nuclear localization would enhance androgen responsiveness. Here, we show that FlnA nuclear localization induced apoptosis in CRPC cells during ADT, identifying it as a treatment tool in advanced CaP. Significantly, the natural product genistein-combined-polysaccharide (GCP) had a similar effect. Investigation of the mechanism of GCP-induced apoptosis showed that GCP induced FlnA cleavage and nuclear localization, and that apoptosis resulting from GCP treatment was mediated by FlnA nuclear localization. Two main components of GCP are genistein and daidzein: the ability of GCP to induce G2 arrest was due to genistein whereas sensitivity to ADT stemmed from daidzein; hence both were needed to mediate GCP's effects. FlnA cleavage is regulated by its phosphorylation; we show that ADT enhanced FlnA phosphorylation, which prevented its cleavage, whereas GCP inhibited FlnA phosphorylation, thereby sensitizing CaP cells to ADT. In a mouse model of CaP recurrence, GCP, but not vehicle, impeded relapse following castration; indicating that GCP, when administered with ADT, interrupted the development of CRPC. These results demonstrate the efficacy of GCP in promoting FlnA nuclear localization and enhancing androgen responsiveness in CaP.

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Section: Discussionmentioning

confidence: 99%

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

Mooso¹,

Vinall²,

Tepper³

et al. 2012

Endocrine-Related Cancer

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“…DU-145 and PC-3 cells were grown in 24-well plates and co-transfected with 150 ng/well of pFN10A-AR, pFN11A-AR and the Gal4 reporter construct pGL4.31. After transfection, cells were cultured and luciferase activities were determined as recently described [28]. …”

Section: Methodsmentioning

confidence: 99%

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells

et al. 2012

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BackgroundNitric oxide (NO) and its oxidative reaction products have been repeatedly shown to block steroid receptor function via nitrosation of zinc finger structures in the DNA-binding domain (DBD). In consequence NO-donors could be of special interest for the treatment of deregulated androgen receptor(AR)-signaling in castration resistant prostate cancer (CRPC).MethodsProstate cancer (PCa) cells were treated with JS-K, a diazeniumdiolate derivate capable of generating large amounts of intracellular NO following activation by glutathione S-transferase. Generation of NO was determined indirectly by the detection of nitrate in tissue culture medium or by immunodetection of nitrotyrosine in the cytoplasm. Effects of JS-K on intracellular AR-levels were determined by western blotting. AR-dimerization was analyzed by mammalian two hybrid assay, nuclear translocation of the AR was visualized in PCa cells transfected with a green fluorescent AR-Eos fusion protein using fluorescence microscopy. Modulation of AR- and WNT-signalling by JS-K was investigated using reporter gene assays. Tumor cell proliferation following JS-K treatment was measured by MTT-Assay.ResultsThe NO-releasing compound JS-K was shown to inhibit AR-mediated reporter gene activity in 22Rv1 CRPC cells. Inhibition of AR signaling was neither due to an inhibition of nuclear import nor to a reduction in AR-dimerization. In contrast to previously tested NO-donors, JS-K was able to reduce the intracellular concentration of functional AR. This could be attributed to the generation of extremely high intracellular levels of the free radical NO as demonstrated indirectly by high levels of nitrotyrosine in JS-K treated cells. Moreover, JS-K diminished WNT-signaling in AR-positive 22Rv1 cells. In line with these observations, castration resistant 22Rv1 cells were found to be more susceptible to the growth inhibitory effects of JS-K than the androgen dependent LNCaP which do not exhibit an active WNT-signaling pathway.ConclusionsOur results suggest that small molecules able to inhibit WNT- and AR-signaling via NO-release represent a promising platform for the development of new compounds for the treatment of CRPC.

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“…Although this would usually favour AR transcriptional inactivation, the situation may be different in a particular cellular context; exogenous overexpression of NCOR1 and NCOR2 can increase AR transcriptional activity, possibly due to an impaired AR/co-repressor interaction [81]. Another study found altered recruitment to AR but also loss of expression of NCOR1/2 in CWR22R castration-resistant cells compared to the androgen-dependent CWR22 [82].…”

Section: Co-regulator Alterations and Aberrant Transcriptionmentioning

confidence: 99%

Therapy escape mechanisms in the malignant prostate

Santer

Erb

McNeill

2015

Seminars in Cancer Biology

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Androgen receptor (AR) is the main target for prostate cancer therapy. Clinical approaches for AR inactivation include chemical castration, inhibition of androgen synthesis and AR antagonists (anti-androgens). However, treatment resistance occurs for which an important number of therapy escape mechanisms have been identified. Herein, we summarise the current knowledge of molecular mechanisms underlying therapy resistance in prostate cancer. Moreover, the tumour escape mechanisms are arranged into the concepts of target modification, bypass signalling, histologic transformation, cancer stem cells and miscellaneous mechanisms. This may help researchers to compare and understand same or similar concepts of therapy resistance in prostate cancer and other cancer types.

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Inability of NCoR/SMRT to repress androgen receptor transcriptional activity in prostate cancer cell lines

Cited by 13 publications

References 22 publications

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

Enhancing the effectiveness of androgen deprivation in prostate cancer by inducing Filamin A nuclear localization

JS-K, a glutathione/glutathione S-transferase-activated nitric oxide releasing prodrug inhibits androgen receptor and WNT-signaling in prostate cancer cells

Therapy escape mechanisms in the malignant prostate

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