SYNERGISTIC ACTIVATION OF ANDROGEN RECEPTOR BY ANDROGEN AND LUTEINIZING-HORMONE-RELEASING HORMONE IN PROSTATIC-CARCINOMA CELLS

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