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Relationship between serum response factor and androgen receptor in prostate cancer.

ABSTRACT: Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR.Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry.To investigate AR involvement in SRF response to androgen, AR expression was down-regulated using siRNA. This resulted in the abrogation of SRF induction post-DHT. Moreover, DHT stimulation failed to induce SRF transcriptional activity in AR-negative PC346 DCC cells, which was only restored following AR over-expression. Next, SRF expression was down-regulated by siRNA, resulting in AR increased transcriptional activity in castrate-resistant LNCaP Abl cells but not in the parental LNCaP. This negative feedback loop in the resistant cells was confirmed by immunohistochemistry which showed a negative correlation between AR and SRF expression in CRPC bone metastases and a positive correlation in androgen-naïve prostatectomies. Cell proliferation was next assessed following SRF inhibition, demonstrating that SRF inhibition is more effective than AR inhibition in castrate-resistant cells.Our data support SRF as a promising therapeutic target in combination with current treatments.

SUBMITTER: Prencipe M

PROVIDER: S-EPMC4579008 | biostudies-literature | 2015 Nov

REPOSITORIES: biostudies-literature

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Relationship between serum response factor and androgen receptor in prostate cancer.

Prencipe Maria M O'Neill Amanda A O'Hurley Gillian G Nguyen Lan K LK Fabre Aurelie A Bjartell Anders A Gallagher William M WM Morrissey Colm C Kay Elaine W EW Watson R William RW

The Prostate 20150807 15

<h4>Background</h4>Serum response factor (SRF) is an important transcription factor in castrate-resistant prostate cancer (CRPC). Since CRPC is associated with androgen receptor (AR) hypersensitivity, we investigated the relationship between SRF and AR.<h4>Materials and methods</h4>Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry.<h4>Results</h4>To investigate ...[more]

PMID: 26250344

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Project description:BackgroundAt present, androgen deprivation therapy (ADT) is still the standard regimen for patients with metastatic and locally advanced prostate cancer (PCa). The level of androgen receptor splice variant-7 (AR-V7) in men with castration-resistant prostate cancer (CRPC) has been reported to be elevated compared with that in patients diagnosed with hormone-sensitive prostate cancer (HSPC).AimHerein, we performed a systematic review and cumulative analysis to evaluate whether the expression of AR-V7 was significantly higher in patients with CRPC than in HSPC patients.MethodsThe commonly used databases were searched to identify the potential studies reporting the level of AR-V7 in CRPC and HSPC patients. The association between CRPC and the positive expression of AR-V7 was pooled by using the relative risk (RR) with the corresponding 95% confidence intervals (CIs) under a random-effects model. For detecting the potential bias and the heterogeneity of the included studies, sensitivity analysis and subgroup analysis were performed. Publication bias was assessed Egger's and Begg's tests. This study was registered on PROSPERO (ID: CRD42022297014).ResultsThis cumulative analysis included 672 participants from seven clinical trials. The study group contained 354 CRPC patients, while the other group contained 318 HSPC patients. Pooled results from the seven eligible studies showed that the expression of positive AR-V7 was significantly higher in men with CRPC compared to those with HSPC (RR = 7.55, 95% CI: 4.61-12.35, p < 0.001). In the sensitivity analysis, the combined RRs did not change substantially, ranging from 6.85 (95% CI: 4.16-11.27, p < 0.001) to 9.84 (95% CI: 5.13-18.87, p < 0.001). In the subgroup analysis, a stronger association was detected in RNA in situ hybridization (RISH) measurement in American patients, and those studies were published before 2011 (all p < 0.001). There was no significant publication bias identified in our study.ConclusionEvidence from the seven eligible studies demonstrated that patients with CRPC had a significantly elevated positive expression of AR-V7. More investigations are still warranted to clarify the association between CRPC and AR-V7 testing.Systematic review registrationhttps://www.crd.york.ac.uk/prospero/, identifier CRD42022297014.

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Relationship between serum response factor and androgen receptor in prostate cancer.

Publications

Relationship between serum response factor and androgen receptor in prostate cancer.

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