Endocrine Abstracts

Phosphorylation of the Androgen Receptor (AR), has been shown to play an important role in directly modulating AR activity. However, the full extent of which protein kinases are involved in the regulation of the AR remains unknown. In order to address which kinases are important in the regulation of AR activity in both androgen sensitive and independent prostate cancer (PCa), a comprehensive siRNA kinome screen was performed. AR transcriptional regulation was evaluated using an AREIII-PSA Luciferase gene reporter assay in LNCaP and LNCaP-AI cell lines. Following parameter optimisation, the siRNA kinome screen identified multiple novel kinases involved in the regulation of AR transcriptional activity. Subsequent candidate validation led to the identification of a novel threonine/serine kinase, found to be critically involved in AR transcriptional activation. Both siRNA mediated KD and pharmacological antagonism, suppressed AR mediated transcriptional activation, as well as inhibiting PCa cell proliferation, including colony formation potential. Our comparative analysis of androgen sensitive and independent cells, indicates that this kinase is a promising therapeutic target in models of PCa. Subsequent evaluation of these kinase targets will help to discern novel mechanisms involved in AR regulation, as well as facilitate the development of more effective treatments for PCa.

Funding: by Prostate Cancer UK.

Presenting Author: Scott Walker, Northern Institute for Cancer Research, Paul O’Gorman Building, The Medical School, Newcastle University, Newcastle upon Tyne, NE2 4HH, UK. Email: [email protected].