An Inhibitory Insulin-Like Growth Factor Binding Protein (In-Igfbp) From Human Prostatic Cell Conditioned Medium Reveals N-Terminal Sequence Identity With Bone Derived in-Igfbp

Abstract

Insulin-like growth factor binding proteins (IGFBPs), are produced by several cell types, are present in biological fluids, and may function in modulating insulin-like growth factor (IGF) biological activities. Recently the presence of multiple IGFBPs was reported in seminal fluid, suggesting that IGFBPs are produced by prostatic epithelium. We have found that human prostatic tumor cells of the PC3 cell line produce an IGFBP. PC3-IGFBP was purified to homogeneity using sequential IGF I affinity and HPLC C4 reverse phase chromatographies. Chemical cross-linking of PC3-IGFBP to 125I-IGF I revealed a molecular weight of 25 kDa. Its N-terminal sequence and amino-acid composition were highly homologous to that of a recently described 25 kDa inhibitory IGFBP (In-IGFBP), produced by osteoblasts in vitro. PC3-IGFBP inhibited basal and IGF II-stimulated bone cell DNA synthesis. We conclude that the PC3-IGFBP is very similar, if not identical to the osteoblast-derived In-IGFBP. Expression of PC3-IGFBP by metastatic human prostate tumor cells thus might affect the osteoblast proliferation that is induced by metastatic prostatic carcinoma. The PC3-IGFBP may be similar to a 24 kDa IGFBP described in seminal fluid and thus may be important in the regulation of cell proliferation in the male reproductive tract.

Insulin-like Growth Factor (IGF)-binding Protein-3 Induces Apoptosis and Mediates the Effects of Transforming Growth Factor-β1 on Programmed Cell Death through a p53- and IGF-independent Mechanism

“…The role of IGFBP-3 as a growth-inhibitory protein has been previously demonstrated by us and others in various cell types (9,(12)(13)(14)(15)(16)(17). Initially, IGFBP-3 was thought to inhibit growth by binding to IGFs and sequestering them from their receptor.…”

“…In addition to regulating the availability of free IGFs and, therefore, their mitogenic activity (1)(2)(3)(4), IGFBPs also play an important role in directly regulating cell growth. These independent cell growthregulatory effects of IGFBPs have been shown to be either growth-inducing (5-10), or growth-inhibiting (9,(12)(13)(14)(15)(16)(17).…”

Liver-derived IGF1 enhances the androgenic response in prostate

“…In vitro studies have demonstrated that several components of the IGF1 system are involved in the regulation of the growth of prostate-derived cells (Perkel et al 1990, Cohen et al 1991, 1994a. In primary culture, the prostatic epithelial cells express the IGF1 receptor and IGF1 stimulates them to proliferate and to produce IGFBPs into the medium (Perkel et al 1990, Cohen et al 1991.…”

“…In primary culture, the prostatic epithelial cells express the IGF1 receptor and IGF1 stimulates them to proliferate and to produce IGFBPs into the medium (Perkel et al 1990, Cohen et al 1991. Prostatic stromal cells also express the IGF1 receptor (Cohen et al 1994a,b,c), and there is local production of IGF1 in these cells (Kaplan et al 1999, Meinbach & Lokeshwar 2006.…”

Posttranslational regulation of insulin-like growth factor binding protein-4 in normal and transformed human fibroblasts. Insulin-like growth factor dependence and biological studies.

“…It is secreted by a number of different cell types in vitro and IGFBP-4 mRNA is expressed in a variety of tissues (6,7,(22)(23)(24)(25)(26)(27)(28)(29). Although its precise biological function is unknown, IGFBP-4 has been implicated as a potent inhibitor ofIGF action in bone and in other systems (8,22,26,(30)(31)(32). Recently, we reported that, in contrast to an increase in IGFBP-3, treatment of normal human fibroblasts and human osteoblast-like cells with IGF-I or IGF-II led to a marked reduction in the levels of 24-kD IGFBP-4 detected in the cell-conditioned medium (25,33).…”