Growth regulation of prostatic stromal cells by prostate-specific antigen.
BACKGROUND
Prostate-specific antigen (PSA) is a serine protease that can cleave insulin-like growth factor-binding protein-3 (IGFBP3), thereby decreasing its affinity for insulin-like growth factor-I (IGF-I). Dissociation of the IGF-I-IGFBP3 complex renders IGF-I available to bind to its receptor and stimulates cellular proliferation. We evaluated the potential for PSA to modulate the effects of IGF-I and IGFBP3 on the proliferation of human benign prostatic hyperplasia (BPH)-derived fibromuscular stromal cells in primary cultures.


METHODS
We cultured BPH-derived stromal cells for 48 hours in serum-free RPMI-1640 medium supplemented with 0.2% bovine serum albumin and studied the effects of IGF-I, IGFBP3, PSA, and ZnCl(2) at varying concentrations. Differences in cell growth between control and treated cultures were evaluated by use of Dunnett's test. Concentration-related trends were evaluated by linear regression of log-transformed concentrations of test reagents on BPH-derived stromal cell number responses. Statistical tests were two-sided.


RESULTS
We observed a concentration-dependent proliferative response of BPH-derived stromal cells to IGF-I. IGFBP3 inhibited this response in a concentration-dependent fashion. IGFBP3 alone had no effect on stromal cell proliferation. When stromal cells were incubated with PSA alone or with PSA, IGF-I, and IGFBP3, an increase in stromal cell numbers that was dependent on PSA concentration was evident in both instances. Zinc, an endogenous inhibitor of PSA enzymatic activity, was able to attenuate the stimulatory effect of PSA at intraprostatic physiologic concentrations.


CONCLUSIONS
These results are consistent with the idea that PSA can modulate in vitro interactions between IGF-I and IGFBP3 and suggest that PSA may play a role in the regulation of human prostatic fibromuscular cell growth.
Sutkowski
D M
DM
Lilly Research Laboratories, a Division of Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN 46285, USA.
Goode
R L
RL
Baniel
J
J
Teater
C
C
Cohen
P
P
McNulty
A M
AM
Hsiung
H M
HM
Becker
G W
GW
Neubauer
B L
BL
D002455:Cell Division; D002478:Cells, Cultured; D002712:Chlorides / Q000378:metabolism*; D002918:Chymotrypsin / Q000378:metabolism; D006801:Humans; D018972:Insulin-Like Growth Factor Binding Protein 3 / Q000378:metabolism*; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D008297:Male; D011467:Prostate / Q000254:growth & development* / Q000378:metabolism*; D017430:Prostate-Specific Antigen / Q000378:metabolism*; D011470:Prostatic Hyperplasia / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D017967:Zinc Compounds / Q000378:metabolism*
D002712:Chlorides; D018972:Insulin-Like Growth Factor Binding Protein 3; D011994:Recombinant Proteins; D017967:Zinc Compounds; D007334:Insulin-Like Growth Factor I; C016837:zinc chloride; D002918:Chymotrypsin; C117608:alpha-chymotrypsin; D017430:Prostate-Specific Antigen