Synergistic activation of androgen receptor by androgen and luteinizing hormone-releasing hormone in prostatic carcinoma cells

BACKGROUND. We investigated modulation of androgen receptor (AR) activity in prostatic tumor cells by luteinizing hormone-releasing hormone (LHRH)-induced increase of the intracellular cyclic adenosine monophosphate (cAMP) level. METHODS. AR transactivation activity was assessed in transiently transfected DU-145 and in LNCaP cells. RESULTS. LHRH and cAMP derivative, respectively, induced reporter gene activity to about 15% of the maximal level in DU-145 cells transfected with an AR expression vector and an androgen-inducible reporter gene. LHRH or the cAMP analogue acted synergistically in combination with low concentrations of androgen thus lowering the androgen concentration required for maximal AR activation by a factor of 100. A similar activation of the AR by cAMP analog-Lie was observed in LNCaP cells when enhancement of androgen-induced secretion of prostate-specific antigen was determined. The two nonsteroidal antiandrogens hydroxyflutamide and Casodex(R) inhibited reporter gene activity. CONCLUSIONS. The AR is synergistically activated by low doses of androgen and LHRH or the second messenger cAMP. This may have implications for the treatment of advanced prostate cancer. (C) 1997 Wiley-Liss, Inc.