Biologically active steroids activate receptor-bound human sex hormone-binding globulin to cause LNCaP cells to accumulate adenosine 3',5'-monophosphate.
The binding of human sex hormone-binding globulin (SHBG) to a human prostatic cancer cell line (LNCaP) and the results of that binding were examined. Membranes derived from LNCaP cells bound unliganded SHBG on two sets of sites whose affinities were: Ka1 = 3.1 +/- 1.6 x 10(10) M-1 and Ka2 = 8.7 +/- 4.3 x 10(6) M-1. Intact cells also bound SHBG, but even after 6 h, less than 10% of specifically bound SHBG was internalized. This observation speaks against a role for the membrane binding of SHBG in steroid transport across cell membranes. When LNCaP cells were prebound with SHBG, addition of dihydrotestosterone or estradiol resulted in a dose-dependent increase in intracellular cAMP. SHBG in the absence of steroids or dihydrotestosterone in the absence of SHBG was without effect. 2-Methoxyestradiol, a steroid metabolite without biological activity, but which binds to SHBG more tightly than does estradiol, was also without effect. These observations demonstrate a potentially important role for SHBG as a regulator of cell function. They also demonstrate an additional mode of action of steroid hormones, one that does not require that the steroid interact with a steroid receptor.
Nakhla
A M
AM
Department of Medicine, St. Luke's/Roosevelt Hospital Center, College of Physicians and Surgeons, Columbia University New York, New York 10019.
Khan
M S
MS
Rosner
W
W
D000077584:2-Methoxyestradiol; D000262:Adenylyl Cyclases / Q000378:metabolism; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D000242:Cyclic AMP / Q000378:metabolism*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000031:analogs & derivatives / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008297:Male; D011471:Prostatic Neoplasms; D011956:Receptors, Cell Surface / Q000378:metabolism*; D012738:Sex Hormone-Binding Globulin / Q000378:metabolism*; D014407:Tumor Cells, Cultured / Q000187:drug effects / Q000378:metabolism*
D011956:Receptors, Cell Surface; D012738:Sex Hormone-Binding Globulin; C063572:sex hormone-binding globulin receptor; D013196:Dihydrotestosterone; D004958:Estradiol; D000077584:2-Methoxyestradiol; D000242:Cyclic AMP; D000262:Adenylyl Cyclases