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D Dart, Oncology, Imperial College London, London, United Kingdom
B Spencer-Dene, Histopathology, Imperial College London, London, United Kingdom
S Gamble, Oncology, Imperial College London, London, United Kingdom
J Waxman, Oncology, Imperial College London, London, United Kingdom
C Bevan, Oncology, Imperial College London, London, W12 0NN, United Kingdom

Correspondence: Charlotte Bevan, Email: charlotte.bevan{at}imperial.ac.uk

Abstract

Current hormonal therapies for prostate cancer are effective initially but inevitably tumours progress to an advanced, metastatic stage, often referred to as androgen-independent. However, the androgen receptor (AR) signalling pathway is still key for their growth. It is speculated that tumours escape hormonal control via reduction of corepressor proteins. Manipulating such proteins is thus a potential therapeutic strategy to halt or even reverse tumour progression. We aimed to elucidate the effects of altering levels of the AR corepressor and androgen target protein prohibitin on prostate tumour growth. Prostate cancer cells incorporating an integrated androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown prohibitin were generated and used to assess effects on androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. Prohibitin overexpression inhibited AR activity and PSA expression as well as androgen-dependent growth of cells, inducing rapid accumulation in G0/G1. Conversely, reduction of prohibitin increased AR activity, PSA expression, androgen-mediated growth and S-phase entry. In vivo, doxycycline-induced prohibitin regulation resulted in marked changes in AR activity, and showed significant effects upon tumour growth. Overexpression led to tumour growth arrest and protection from hormonal starvation, whereas RNAi knockdown resulted in accelerated tumour growth, even in castrated mice. This study provides proof of principle that (i) reduction of prohibitin promotes both androgen-dependent and androgen-independent tumour growth and (ii) altering AR activity via increasing levels or activity of corepressors is a valid therapeutic strategy for advanced prostate cancer.