Anti-Proliferative Actions of IGFBP-3 and Its Proteolytic Fragments in Human Prostate Cancer

摘要

Insulin-like growth factor binding protein-3 (IGFBP-3), the predominant IGF carrier protein in circulation, is post-translationally modified in vivo by IGFBP-3 protease(s) into a number of fragments. Based on the ascertained and predicted recognition sites for known IGFBP-3 proteases, like prostate specific antigen, recombinant intact and proteolytic fragments of IGFBP-3 were generated. The NH2- and COOH-terminal fragments bound both IGF and insulin specifically, albeit with significantly reduced affinity for IGF but higher affinity for insulin, when compared to IGFBP-3. IGFBP-3 and (1-97)IGFBP-3 NH2-terminal fragment inhibited IGFIR activation. However, unlike the 1-97 fragment, the COOH terminal fragments of IGFBP-3 retained their ability to associate with the cell surface similar to intact IGFBP-3. Using IGF analogs, we demonstrate that IGFBP-3 does not directly interact with the IGFIR. Further, the role of endogenous IGFBP-3 on prostate cell growth was evaluated by stable transfection of human IGFBP-3 cDNA into a tumorigenic and metastatic prostate epithelial cell line (M12). IGFBP-3 causes significant growth inhibition, induces early apoptosis in the cancer cells and causes decreased tumor formation in vivo. These data suggest that IGFBP-3 has a suppressive effect on prostate cancer development and various forms of IGFBP-3 fragments resulting from proteolysis may have different effects on the IGF-IGFIR axis, as well as potential IGF-independent actions.