Editors' ChoiceAndrogen Receptors

A New Route to Androgen Receptor Activation

Science's STKE  14 Jan 2003:
Vol. 2003, Issue 165, pp. tw21-TW21
DOI: 10.1126/stke.2003.165.tw21

Metzger et al. investigated signaling to the androgen receptor (AR) in cultured HEK 293 cells expressing the AR and uncovered a novel pathway linking RhoA to AR activation that may have implications for the therapy of prostate cancer. AR stimulates the growth and survival of prostate cancer cells through androgen-dependent mechanisms. However, prostate cancer frequently progresses after androgen ablation therapy and in the presence of AR antagonists. Metzger et al. used pharmacological analysis combined with expression of constitutively active or inhibitory mutants of molecules potentially involved in Rho signaling pathways to implicate the RhoA effector protein kinase C-related kinase (PRK1) in Rho-mediated stimulation of androgen-dependent activation of an AR target gene reporter. A constitutively active PRK1 mutant also stimulated ligand-dependent activation of the progesterone receptor and the mineralocorticoid receptor. Immunofluorescence analysis revealed ligand-dependent translocation of AR and PRK1 to the nucleus. Western analysis of immunoprecipitates demonstrated ligand-dependent association between AR and PRK1 expressed in HEK 293 cells, as well as endogenous AR and PRK1 from primary human prostate tumors. The authors used AR deletion mutants to identify transactivation unit 5 (TAU-5) as a transactivation domain that mediates PRK-inducible transcriptional activation. Immunohistochemical and Western analysis indicated that PRK1 was overexpressed in prostate tumors. Although PRK1 stimulation of AR transcription activity was ligand-dependent, stimulation occurred in the presence of very low concentrations of adrenal androgens, which would remain after androgen ablation therapy, or with the AR antagonist cyproterone acetate. This occurrence suggests that this pathway may play an important role in the progression of prostate cancer seen after androgen ablation or treatment with androgen antagonists.

E. Metzger, J. M. Müller, S. Ferrari, R. Buettner, R. Schüle, A novel inducible transactivation domain in the androgen receptor: Implications for PRK in prostate cancer. EMBO J. 22, 270-280 (2003). [Abstract] [Full Text]