Relationship between serum response factor and androgen receptor in prostate cancer

Maria Prencipe, Amanda O'Neill, Gillian O'Hurley, Lan K Nguyen, Aurelie Fabre, Anders Bjartell, William M Gallagher, Colm Morrissey, Elaine W Kay, R William G Watson

Research output: Contribution to journalArticleResearchpeer-review

3 Citations (Scopus)

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-naive 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. (c) 2015 Wiley Periodicals, Inc.
Original languageEnglish
Pages (from-to)1704-1717
Number of pages14
JournalThe Prostate
Volume75
Issue number15
DOIs
Publication statusPublished - 1 Nov 2015
Externally publishedYes

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