scholarly journals Hormonal Therapy Promotes Hormone-Resistant Phenotype by Increasing DNMT Activity and Expression in Prostate Cancer Models

Endocrinology ◽  
2011 ◽  
Vol 152 (12) ◽  
pp. 4550-4561 ◽  
Author(s):  
Giovanni Luca Gravina ◽  
Francesco Marampon ◽  
Margherita Piccolella ◽  
Marcella Motta ◽  
Luca Ventura ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Hormonal Therapy ◽  
Standard Condition ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
In Vivo Models ◽  
Resistant Phenotype ◽  
Expression And Activity

We hypothesized that hormonal therapy favors the development of the hormone-resistant phenotype through epigenetic mechanisms. Human prostate cancer tissues and in vitro and in vivo models were used to verify this hypothesis. We demonstrated that tumor cells continuously treated with bicalutamide (BCLT) or cultured in androgen-depleted medium progressively acquire higher DNA methyltransferase (DNMT) activity and expression than cells cultured in standard condition. Increased DNMT expression and activity also paralleled the up-regulation of truncated AR isoforms, which favors the development of the hormone-resistant phenotype. After androgen stimulation with 10−12m dihydrotestosterone, DNMT activity was significantly reduced in comparison with hormonal therapy. Consistent with these observations, the silencing of DNMT3a and DNMT3b significantly decreased the DNMT activity levels. These findings were also directly correlated with phosphatase and tensin homolog down-regulation and activation of ERK and phosphatidylinositol 3-kinases/AKT8 virus oncogene cellular homolog pathways. The use of a pan-DNMT inhibitor (5-Azacitidine) greatly reduced the development of the hormone-resistant phenotype induced by long-term BCLT treatment, and this finding correlated with low DNMT activity. The regulation of DNMT activity was, in some measure, dependent on the androgen receptor, as small interfering RNA treatment targeting the androgen receptor greatly decreased the modulation of DNMT activity under androgenic and antiandrogenic stimulation. These observations were correlated in vivo in patients, as demonstrated by immunohistochemistry. Patients treated by BCLT before surgery had higher DNMT3a and DNMT3b expression than patients who had not undergone this treatment. Our findings provide evidence of a relationship between the castration-resistant phenotype and DNMT expression and activity in human prostate cancer.

scholarly journals PXD101 potentiates hormonal therapy and prevents the onset of castration-resistant phenotype modulating androgen receptor, HSP90, and CRM1 in preclinical models of prostate cancer

2013 ◽  
Vol 20 (3) ◽  
pp. 321-337 ◽  
Author(s):  
Giovanni Luca Gravina ◽  
Francesco Marampon ◽  
Paola Muzi ◽  
Andrea Mancini ◽  
Margherita Piccolella ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Hormonal Therapy ◽  
Disease Stage ◽  
Castration Resistant ◽  
Resistant Phenotype ◽  
Expression Activity ◽  
Gsk 3Β ◽  
Functional Knockdown ◽  
Expression And Activity

Aberrant activation or ‘reactivation’ of androgen receptor (AR) during androgen ablation therapy shows a potential cause for the development of castration-resistant prostate cancer. This study tested the hypothesis that PXD101, a potent pan histone deacetylase (HDAC) inhibitor, may prevent onset of castration-resistant phenotype and potentiate hormonal therapy. A panel of human prostate cancer cells with graded castration-resistant phenotype and in vivo models were used to verify this hypothesis. In this report, we demonstrated that hormonal manipulation favors the onset of castration-resistant phenotype increasing HDAC expression and activity as well as modulating expression and activity of AR, EGFR, HER2, and Akt. Consistent with these observations, the functional knockdown of HDACs by PXD101 prevented the onset of castration-resistant phenotype with a significant downregulation of AR, EGFR, HER2, and Akt expression/activity. The dysregulation of functional cooperation between HDAC6 with hsp90, on the one hand, and between GSK-3β with CRM1, on the other hand, may explain the biological effects of PXD101. In this regard, the HDAC6 silencing or the functional knockdown of hsp90 by 17AAG resulted in the selective downregulation of AR, EGFR, HER2, and Akt expression/activity, while the decreased phosphorylation of GSK-3β mediated by PXD101 increased the nuclear expression of CRM1, which in turn modified the AR and survivin recycling with increased caspase 3 activity. HDAC inhibitors retain the ability to prevent the onset of castration-resistant phenotype and, therefore, merit clinical investigation in this setting. However, additional data are needed to develop clinical treatment strategies for this disease stage.

In vivo amplification of the androgen receptor gene and progression of human prostate cancer

1995 ◽  
Vol 9 (4) ◽  
pp. 401-406 ◽  
Author(s):  
Tapio Visakorpi ◽  
Eija Hyytinen ◽  
Pasi Koivisto ◽  
Minna Tanner ◽  
Riitta Keinänen ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Receptor Gene ◽  
Androgen Receptor Gene ◽  
Human Prostate ◽  
Human Prostate Cancer

scholarly journals GREB1 amplifies androgen receptor output in human prostate cancer and contributes to antiandrogen resistance

eLife ◽  
2019 ◽  
Vol 8 ◽  
Author(s):  
Eugine Lee ◽  
John Wongvipat ◽  
Danielle Choi ◽  
Ping Wang ◽  
Young Sun Lee ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Target Gene ◽  
Prostate Cancer Cell ◽  
Human Prostate ◽  
Genomic Alteration ◽  
Human Prostate Cancer ◽  
Genomic Amplification ◽  
Human Prostate Cancer Cell

Genomic amplification of the androgen receptor (AR) is an established mechanism of antiandrogen resistance in prostate cancer. Here, we show that the magnitude of AR signaling output, independent of AR genomic alteration or expression level, also contributes to antiandrogen resistance, through upregulation of the coactivator GREB1. We demonstrate 100-fold heterogeneity in AR output within human prostate cancer cell lines and show that cells with high AR output have reduced sensitivity to enzalutamide. Through transcriptomic and shRNA knockdown studies, together with analysis of clinical datasets, we identify GREB1 as a gene responsible for high AR output. We show that GREB1 is an AR target gene that amplifies AR output by enhancing AR DNA binding and promoting EP300 recruitment. GREB1 knockdown in high AR output cells restores enzalutamide sensitivity in vivo. Thus, GREB1 is a candidate driver of enzalutamide resistance through a novel feed forward mechanism.

Lipid nanoparticle siRNA systems for silencing the androgen receptor in human prostate cancer in vivo

2012 ◽  
Vol 131 (5) ◽  
pp. E781-E790 ◽  
Author(s):  
Justin B. Lee ◽  
Kaixin Zhang ◽  
Yuen Yi C. Tam ◽  
Ying K. Tam ◽  
Nathan M. Belliveau ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Androgen Receptor ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Lipid Nanoparticle

629: Novel Laser Activated Gold Nanoshell Thermal Ablation of Human Prostate Cancer in Vivo

2007 ◽  
Vol 177 (4S) ◽  
pp. 210-211 ◽  
Author(s):  
Joshua M. Stern ◽  
Jennifer Stanfield ◽  
Jer-Tsang Hsieh ◽  
Jeffrey A. Cadeddu
Keyword(s):  
Prostate Cancer ◽  
Thermal Ablation ◽  
Human Prostate ◽  
Human Prostate Cancer ◽  
Gold Nanoshell
Sign in / Sign up

Export Citation Format

Share Document