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Sex Hormone-Binding Globulin Mediates Prostate Androgen Receptor Action via a Novel Signaling Pathway

Department of Biochemistry and Physiology, Department of Laboratory Animal Resources, Merck Research Laboratories, Rahway, New Jersey 07065; and Department of Medicine, St. Luke’s/Roosevelt Hospital Center, College of Physicians and Surgeons, Columbia University New York, New York 10019

Address all correspondence and requests for reprints to: Dr. V. Ding, Department of Molecular Endocrinology, Merck Research Laboratories (RY80W-243), P.O. Box 2000, Rahway, New Jersey 07065. E-mail: victor-ding{at}merck.com

Estradiol (E₂) and 5-androstan-3,17ß-diol (3-diol) have been implicated in prostate hyperplasia in man and dogs, but neither of these steroids bind to androgen receptors (ARs). Recently, we reported that E₂ and 3-diol stimulated generation of intracellular cAMP via binding to a complex of sex hormone-binding globulin (SHBG) and its receptor (R_SHBG) on prostate cells. We speculated that this pathway, involving steroids normally found in the prostate, was involved in the indirect activation of ARs. Using the dog as a model to test this hypothesis in normal prostate, we investigated whether E₂, 3-diol, and SHBG stimulated the production of the androgen-responsive protein, arginine esterase (AE), the canine equivalent of human prostate-specific antigen. In cultured dog prostate tissue preincubated with SHBG, E₂ and 3-diol stimulated AE activity. These effects were blocked by hydroxyflutamide, an AR antagonist, and by 2-methoxyestradiol, a competitive inhibitor of E₂ and 3-diol binding to SHBG. In the absence of exogenous steroids and SHBG, AE also was significantly increased by treatment with forskolin or 8-Bromoadenosine-cAMP. These observations support the hypothesis that in normal prostate, E₂ and 3-diol can amplify or substitute for androgens, with regard to activation of the AR via the R_SHBG by a signal transduction pathway involving cAMP. Because both E₂ and 3-diol are involved in the pathogenesis of benign prostatic hyperplasia in dogs and implicated in benign prostatic hyperplasia in man, antagonism of the prostatic SHBG pathway may offer a novel and attractive therapeutic target.

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