Insulin-like growth factor-binding protein 5 promotes prostate cancer metastasis and osteoblastic activity by inducing chemokines and activating NF-κB signaling

BACKGROUND: Insulin-like growth factor binding protein 5 (IGFBP5) has been implicated in prostate cancer progression; however, its role in metastasis remains poorly defined. METHODS: IGFBP5 expression and its association with clinicopathological features were evaluated using a tissue microarray containing 72 prostate tumors and 36 adjacent normal tissues. Its metastatic function was assessed through gain- and loss-of-function experiments in PC3 and DU145 prostate cancer cell lines, as well as in vivo via tail-vein injection models. To investigate bone metastasis potential, co-culture assays with osteogenic MC3T3E1 cells and endothelial tube formation assays were conducted. RNA sequencing followed by gene set enrichment analysis (GSEA) was performed to explore underlying molecular mechanisms. RESULTS: IGFBP5 expression was significantly elevated in prostate cancer tissues and positively correlated with higher Gleason scores. Elevated IGFBP5 levels were also associated with increased M2 macrophage infiltration (ρ = 0.514, p < 0.01) and extra-prostatic metastasis. Functional assays demonstrated that IGFBP5 overexpression enhanced epithelial–mesenchymal transition (EMT) marker expression (CDH2, vimentin, Snail), and increased cell migration and invasion, whereas IGFBP5 knockdown suppressed these aggressive phenotypes. In vivo, IGFBP5 overexpression led to a higher number of pulmonary metastatic nodules. Conditioned media from IGFBP5-overexpressing PC3 cells promoted osteogenic mineralization and endothelial tube formation, indicating pro-osteogenic and pro-angiogenic activity. Mechanistic analysis suggested that IGFBP5 facilitates metastasis through activation of NF-κB signaling, promoting EMT and upregulating chemokines such as CXCL8 and CCL2. CONCLUSIONS: IGFBP5 promotes prostate cancer metastasis by enhancing EMT, osteogenesis, and angiogenesis, potentially via NF-κB signaling. These findings highlight IGFBP5 as a promising biomarker and therapeutic target for metastatic prostate cancer.