Mechanism of androgen receptor activation and possible implications for chemoprevention trials

Androgens are pivotal regulators of prostate cell growth, differentiation a nd function, and their actions are believed to be involved in prostate canc er development. The androgen-signaling pathway in the prostate gland is the refore one of the possible sites of intervention in prostate cancer prevent ion efforts. The central element of androgen signaling in the cell is the a ndrogen receptor (AR), a member of the superfamily of nuclear receptors. Bi nding of androgen to its ligand-binding domain transforms the receptor to a n active transcription factor that regulates gene expression by interacting with specific regulatory elements in the promoters of genes. In addition t o this genomic action, the AR also interacts with other signaling pathways through protein-protein interaction, for example with AP-1 or Ets transcrip tion factors. It is not only the action of androgenic hormones, but also th e interactions with growth factor and protein kinase A-signaling pathways t hat can induce activation of AR. Moreover, these ligand-independent activat ors act synergistically together with low concentrations of androgens. The effects of long-term androgen deprivation on androgen signaling have been i nvestigated in the LNCaP cell culture system. Long-term culture in a steroi d-free medium results in a subline showing a hyperreactive AR characterized by increased AR expression and enhanced AR transcriptional activity in an environment with low levels of androgen hormones. It is not yet clear if si milar changes also occur in normal or premalignant prostate epithelial cell s and are thus relevant for prevention trials which interfere with androgen hormone signaling.