The role of transforming growth factor-beta1, -beta2, and -beta3 in androgen-responsive growth of NRP-152 rat prostatic epithelial cells.
We have investigated the role of autocrine/paracrine TGF-beta secretion in the regulation of cell growth by androgens as demonstrated by its inhibition by two androgen response modifiers; the nonsteroidal antiandrogen hydroxyflutamide (OHF), believed to act by inhibiting androgen binding to androgen receptors, or finasteride, an inhibitor of 5alpha-reductase, the enzyme necessary for the conversion of testosterone to 5alpha-dihydrotestosterone (DHT), using the nontumorigenic rat prostatic epithelial cell line NRP-152. Growth of these cells was stimulated three- to sixfold over control by either testosterone or DHT under serum-free culture conditions. This was accompanied by a two- to threefold decrease in the secretion rate of TGF-beta1, -beta2, and -beta3. Finasteride reversed the ability of testosterone but not DHT to stimulate growth and downregulate expression of TGF-beta1, -beta2, and -beta3 in a dose-dependent fashion, suggesting that this activity of testosterone required its conversion to DHT. OHF antagonized the stimulatory effects of DHT on NRP-152 cell growth but could reverse the inhibitory effects of DHT only on TGF-beta2 and TGF-beta3 and not TGF-beta1 secretion. This suggests that either TGF-beta1 regulation by DHT or the androgen antagonism of OHF occurs independent of androgen receptor binding. Neutralizing antibodies to TGF-beta (pantropic and isoform-specific) were able to block the ability of finasteride to antagonize the effects of testosterone nearly completely while only partially inhibiting the antiandrogenic effects of OHF. Thus, the ability of androgens to stimulate growth of NRP-152 cells involves the downregulation of the production of TGF-beta1, -beta2, and -beta3 in addition to other growth-stimulatory mechanisms.
Lucia
M S
MS
Laboratory of Cell Regulation and Carcinogenesis, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
Sporn
M B
MB
Roberts
A B
AB
Stewart
L V
LV
Danielpour
D
D
D000726:Androgen Antagonists / Q000494:pharmacology; D000728:Androgens / Q000494:pharmacology*; D000818:Animals; D000906:Antibodies / Q000276:immunology / Q000494:pharmacology; D002455:Cell Division / Q000187:drug effects*; D002460:Cell Line; D013196:Dihydrotestosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D015536:Down-Regulation / Q000502:physiology; D018120:Finasteride / Q000494:pharmacology; D005485:Flutamide / Q000031:analogs & derivatives / Q000494:pharmacology; D008297:Male; D011467:Prostate / Q000187:drug effects*; D051381:Rats; D013739:Testosterone / Q000037:antagonists & inhibitors / Q000494:pharmacology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
D000726:Androgen Antagonists; D000728:Androgens; D000906:Antibodies; D016212:Transforming Growth Factor beta; D013196:Dihydrotestosterone; C014290:hydroxyflutamide; D013739:Testosterone; D018120:Finasteride; D005485:Flutamide