Am. Nakhla et al., ESTRADIOL ACTIVATES THE PROSTATE ANDROGEN RECEPTOR AND PROSTATE-SPECIFIC ANTIGEN SECRETION THROUGH THE INTERMEDIACY OF SEX HORMONE-BINDING GLOBULIN, The Journal of biological chemistry, 272(11), 1997, pp. 6838-6841
These experiments were designed to examine the relationship between th
e effects of steroid hormones mediated by classic intracellular steroi
d 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) bind
s to a receptor (R(SHBG)) on prostate membranes, The R,,, SHBG complex
is rapidly activated by estradiol to stimulate adenylate cyclase, wit
h a resultant increase in intracellular cAMP. In this paper we examine
the effect of this system on a prostate gene product known to be acti
vated by androgens, prostate-specific antigen, In serum-free organ cul
ture of human prostates, dihydrotestosterone caused an increase in pro
state specific antigen secretion, This event was blocked by the anti-a
ndrogens cyproterone acetate and hydroxyflutamide, In the absence of a
ndrogens, estradiol added to prostate tissue, whose R(SHBG) was occupi
ed by SHBG, reproduced the results seen with dihydrotestosterone. Neit
her estradiol alone nor SHBG alone duplicated these effects. The estra
diol SHBG-induced increase in prostate-specific antigen was not blocke
d by anti-estrogens, but was blocked both by anti-androgens and a ster
oid (2-methoxyestradiol) that prevents the binding of estradiol to SHB
G, Furthermore, an inhibitor of protein kinase A prevented the estradi
ol SHBG-induced increase in prostate-specific antigen but not that whi
ch followed dihydrotestosterone. These data indicate that there is a s
ignaling system that amalgamates steroid-initiated intracellular event
s with steroid dependent occurrences generated at the cell membrane an
d that the latter signaling system proceeds by a pathway that involves
protein kinase A.