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

Abstract

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.

Serum total PSA and free PSA in breast tumors

“…(i) PSA acts as mitogen to breast tissue through of TGF-b (transforming growth factor b), a known mitogen of breast tissue [29] (ii) PSA degrades fibronectin and laminin, the cellular matrix proteins, thereby facilitating local invasion [30] (iii) It increases IGF-1, a proven mitogen of breast tissue [31] (iv) It degrades IGFBP-3, which normally induces apoptosis in breast tissue and its degradation by PSA stimulates tumour progression [32].…”

Insulin-like growth factors and their binding proteins in human colonocytes: preferential degradation of insulin-like growth factor binding protein 2 in colonic cancers

“…IGFBP proteases have been detected for IGFBP-3 in prostatic cancer (Cohen et al, 1994) and IGFBP-4 in osteoblast cell systems (Lalou et al, 1994). A serine protease that specifically degrades IGFBP-5 in fibroblasts has been reported (Nam et al, 1994).…”

Putative role of serum insulin-like growth factor–1 (IGF-1) and IGF binding protein-3 (IGFBP-3) levels in the development of prostate cancer in Arab men

“…In other studies, men with prostate cancer were said to have higher serum IGF-1 levels compared to men with BPH or aged-matched normal men. [31][32][33] A possible explanation for the disparity in our study may be because men with prostate cancer in this study were about a decade older than those with BPH. Serum IGF-1 level declines with age.…”

“…7 Many unanswered questions remain regarding serum IGF-1 and IGFBP-3 levels and risk of prostate cancer. [31][32][33] For example, Kanety et al 32 actually demonstrated lower serum IGF-1 concentrations in patients with prostate cancer; however, their population was composed mainly of patients with advanced disease, who therefore may have had diminished nutritional status leading to lower 35 reported that plasma IGFBP-3 levels were found to be highest in healthy subjects, followed by patients with localized prostate cancer and patients with lymph node metastases while the lowest levels were found in patients with skeletal metastases. The findings from the Arab population with a low incidence of prostate cancer are in agreement with those of Shariat et al 2002.…”