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

Abstract

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 hormonebinding globulin. It is known that unliganded sex hormone-binding globulin (SHBG) binds to a receptor (R SHBG ) on prostate membranes. The R SHBG ⅐SHBG 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 estradiol⅐SHBG-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 estradiol⅐SHBG-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.The standard model of estrogen action posits that hormonal effects are mediated via the intermediacy of intracellular estrogen receptors (ER) 1 (1-4). These receptors have nascent transcriptional activity that is unmasked by estrogens, thus allowing the transcription of specific genes. The exclusivity of this model in accounting for estrogen action is disputed by observations that estrogens may act by non-ER-mediated mechanisms (5-10). Furthermore, the plasticity of the model has had to be modified because of observations that the ER may initiate transcription in the absence of estrogens, so-called ligand-independent activation of transcription (2,(11)(12)(13). Although the data supporting the existence of ligand-independent activation of transcription is substantive, and also has been demonstrated for the progesterone receptor and vitamin D receptor (11,14,15), the physiological role of such activation and/or its relation to ligand-activated transcription remains to be clarified. We have shown previously that estradiol (E 2 ) participates in a signaling system that originates, not within the cell, but at the plasma membrane (5, 16). Through the intermediacy of the plasma protein, sex hormone-binding globulin (SHBG), it causes the generation of cAMP (17)(18)(19). In brief, unli...

Switch from antagonist to agonist of the androgen receptor blocker bicalutamide is associated with prostate tumour progression in a new model system

“…Ligand-independent activation of the AR by growth factors and protein kinase A activators and synergistic effects of these activators and androgen were reported (Culig et al, 1994(Culig et al, , 1997aNazareth and Weigel, 1996). Furthermore, androgen-like effects of epidermal growth factor and keratinocyte growth factor during sexual development and AR-dependent stimulation of PSA secretion in explants of prostate tissue by a cyclic adenosine monophosphate analogue were described (Gupta et al, 1996;Nakhla et al, 1997;Thomson et al, 1997). We aimed to obtain more information on AR activation in LNCaP-abl cells and reduced the influence of serum in subsequent experiments as much as possible.…”

Endogenous sex hormones and the risk of prostate cancer: A prospective study

“…Independent of its role as a carrier protein, unliganded SHBG may also play a role in cell signaling by direct binding to a receptor (R SHBG ), inducing synthesis of cAMP and initiating downstream signaling and genomic effects 40,41 ; under this mechanism, steroids bound to SHBG 42,43 may influence R SHBG -mediated signaling 40,44,45 and cell growth. 46 Similar to our findings, D4-A was unrelated to prostate cancer in most 12,13,15,17,19 but not all previous studies.…”

Androgen receptors in prostate cancer.

“…AR activation in the absence of ligand was demonstrated for MAPK kinase kinase The physiological significance of AR activation by a non-steroidal compound is more convincing if expression of an endogenous AR target gene is up-regulated. Examples of such an effect include stimulation of PSA gene expression by IGF-I and IL-6 in LNCaP cells (Culig et al 1994, Hobisch et al 1998, Chen et al 2000 or by forskolin in prostate explants (Nakhla et al 1997). Thus, non-steroidal activation of the AR is pathophysiologically relevant and it is not a simple reflection of overexpression of AR cDNA.…”