Prostate-specific antigen enhances bioavailability of insulin-like growth factor by degrading insulin-like growth factor binding protein 5

Abstract In the bone matrix, insulin-like growth factors (IGFs) are the most abundant growth factors and IGF binding protein 5 (IGFBP-5) is the major IGFBP. Our previous study suggested that IGFs stored in the bone matrix and prostate-specific antigen (PSA) play an important role in prostate cancer (PC) bone metastasis. However, it is not clear how IGF signaling is activated in the bone microenvironment of PC metastasis. Therefore, we investigated whether PSA degrades IGFBP-5 and enhances biological activity of IGF. Enzymatically active PSA degraded the recombinant IGFBP-5 protein in a dose- and time-dependent manner and a serine protease inhibitor suppressed this degradation. Furthermore, PSA induced IGF-mediated type I IGF receptor phosphorylation that was inhibited by coincubation with IGFBP-5. The present study indicates PSA derived from PC cells can enhance IGF bioavailability in the bone microenvironment of PC metastasis, thereby permitting PC survival and malignant progression in the bone microenvironment.