Relationship between serum response factor and androgen receptor in prostate cancer

Prencipe, MariaMariaPrencipeO'Neill, AmandaAmandaO'NeillO'Hurley, GillianGillianO'HurleyNguyen, Lan K.Lan K.NguyenFabre, AurélieAurélieFabreGallagher, William M.William M.GallagherWatson, R. WilliamR. WilliamWatsonet al.2016-01-282016-08-072015 Wiley2015-11Prostatehttp://hdl.handle.net/10197/7430Background: 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. Materials and Methods: Transcriptional activity was assessed by luciferase assay. Cell proliferation was measured by MTT and flow cytometry. Protein expression in patients was assessed by immunohistochemistry. Results: 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. Conclusion: Our data support SRF as a promising therapeutic target in combination with current treatments. Prostate 75:1704–1717, 2015. © 2015 Wiley Periodicals, Inc.enThis is the author's version of the following article: Prencipe M, O'Neill A;O'Hurley G;Nguyen LK;Fabre A;Bjartell A;Gallagher WM;Morrissey C;Kay EW;Watson RW (2015) "Relationship between serum response factor and androgen receptor in prostate cancer" Prostate, 75(15) : 1704-1717 which has been published in final form at http://dx.doi.org/10.1002/pros.23051.Castrate-resistant prostate cancerSerum response factorAndrogen receptorRelationship between serum response factor and androgen receptor in prostate cancerJournal Article75151704171710.1002/pros.230512016-01-22https://creativecommons.org/licenses/by-nc-nd/3.0/ie/