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 in
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 (PHB) on prostate tumour growth.
Prostate cancer cells incorporating an integrated
androgen-responsive reporter gene and stably expressing vectors to inducibly overexpress or knockdown PHB were generated and used to assess effects on
androgen signalling (by real time imaging) and tumour growth both in culture and in vivo. PHB overexpression inhibited AR activity and
prostate-specific antigen (PSA) expression as well as
androgen-dependent growth of cells, inducing rapid accumulation in G(0)/G(1). Conversely, reduction in PHB increased AR activity, PSA expression,
androgen-mediated growth and S-phase entry. In vivo,
doxycycline-induced PHB 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 in PHB 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.