Maria Prencipe1, Amanda O'Neill1, Gillian O'Hurley2, Lan K Nguyen3, Aurelie Fabre4, Anders Bjartell5, William M Gallagher2,6, Colm Morrissey7, Elaine W Kay8, R William Watson1. 1. UCDSchool of Medicine and Medical Science, Conway Institute of Biomolecular Biomedical Research, University College Dublin, Dublin, Ireland. 2. OncoMark Limited, NovaUCD, Belfield Innovation Park, Dublin, Ireland. 3. Systems Biology Ireland, University College Dublin, Dublin, Ireland. 4. Department of Pathology, St Vincent's University Hospital, Dublin, Ireland. 5. Department of Urology, Sk, å, ne University Hospital, Malm, ö, Sweden. 6. UCD School of Biomolecular and Biomedical Science, Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Dublin, Ireland. 7. Department of Urology, University of Washington, Seattle, Washington, USA. 8. Department of Pathology, RCSI Education and Research Centre, Beaumont Hospital, Dublin, Ireland.
Abstract
BACKGROUND: 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.
BACKGROUND: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 LNCaPAbl 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.
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