Biological effects of prostate specific antigen as an insulin-like growth factor binding protein-3 protease

Prostate specific antigen (PSA) is an insulin-like growth factor (IGF) binding protein-3 (IGFBP-3) protease found in seminal plasma and produced by prostatic epithelial cells (PC-E) in vivo. We examined the effects of PSA-proteolysis of IGFBP-3 on the affinity of IGFBP-3 fragments for IGFs and on the mitogenic action of IGFs on PC-E. Recombinant human IGFBP-3 was cleaved by PSA, then incubated with 125I-IGF-I or -II in the presence of varying concentrations of unlabelled peptides, and then cross-linking electrophoresis and densitometric analysis were performed. While the affinity of IGF-II for the PSA-generated IGFBP-3 fragments fell slightly compared to intact IGFBP-3, the affinity of the PSA-generated IGFBP-3 fragments for IGF-I fell by ten fold. The addition of IGF-I or -II to PC-E in serum-free culture conditions resulted in a two-fold stimulation of cell number compared to control. The presence of IGFBP-3 in the media blocked the IGF-induced stimulation, but had no independent effect in the absence of IGFs. When PSA was added to PC-E cultures to which both IGF-I or -II and IGFBP-3 were added, the inhibitory effects of IGFBP-3 on IGF mitogenesis were reversed. We conclude that PSA decreases the affinity of IGFBP-3 for IGF and can potentiate IGF action in the presence of inhibitory IGFBP-3. This phenomenon may contribute to normal and malignant prostate growth.