Volume 272, Number 11, Issue of March 14, 1997 pp. 6838-6841
©1997 by The American Society for Biochemistry and Molecular Biology, Inc.

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COMMUNICATION:
Estradiol Activates the Prostate Androgen Receptor and Prostate-specific Antigen Secretion through the Intermediacy of Sex Hormone-binding Globulin

(Received for publication, December 23, 1996)

Atif M. Nakhla , Nicholas A. Romas ^§ and William Rosner

From the Departments of  Medicine and ^§ Urology, St. Luke's/Roosevelt Hospital Center, New York, New York 10019 and the College of Physicians and Surgeons, Columbia University, New York, New York 10019

These experiments were designed to examine the relationship between the effects of steroid hormones mediated by classic intracellular steroid hormone receptors and those mediated by a signaling system subserved at the plasma membrane by a receptor for sex hormone-binding globulin. It is known that unliganded sex hormone-binding globulin (SHBG) binds to a receptor (R_SHBG) on prostate membranes. The R_SHBG·SHBG complex is rapidly activated by estradiol to stimulate adenylate cyclase, with a resultant increase in intracellular cAMP. In this paper we examine the effect of this system on a prostate gene product known to be activated by androgens, prostate-specific antigen. In serum-free organ culture of human prostates, dihydrotestosterone caused an increase in prostate specific antigen secretion. This event was blocked by the anti-androgens cyproterone acetate and hydroxyflutamide. In the absence of androgens, estradiol added to prostate tissue, whose R_SHBG was occupied by SHBG, reproduced the results seen with dihydrotestosterone. Neither estradiol alone nor SHBG alone duplicated these effects. The estradiol·SHBG-induced increase in prostate-specific antigen was not blocked by anti-estrogens, but was blocked both by anti-androgens and a steroid (2-methoxyestradiol) that prevents the binding of estradiol to SHBG. Furthermore, an inhibitor of protein kinase A prevented the estradiol·SHBG-induced increase in prostate-specific antigen but not that which followed dihydrotestosterone. These data indicate that there is a signaling system that amalgamates steroid-initiated intracellular events with steroid-dependent occurrences generated at the cell membrane and that the latter signaling system proceeds by a pathway that involves protein kinase A.

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