Nephroblastoma overexpressed (NOV or CCN3) is a secreted matrix-associated protein that belongs to the CCN gene family and is involved in many cellular functions, including growth, differentiation and adhesion. The effect of CCN3 on human prostate cancer cells, however, is unknown. Here, we have shown that CCN3 increased cell migration and intercellular adhesion molecule-1 (ICAM-1) expression in prostate cancer cells. In addition, expression of CCN3 was positively correlated with both cell migration and ICAM-1 expression in human prostate cancer cells. CCN3 activated a signal transduction pathway that included αvβ3 integrin, integrin-linked kinase (ILK), Akt and nuclear factor-kappaB (NF-κB). Reagents that inhibit specific components of this pathway each diminished the ability of CCN3 to effect cell migration and ICAM-1 expression. Moreover, CCN3 increased binding of p65 to an NF-κB-binding element in the ICAM-1 promoter. Finally, knockdown of CCN3 expression markedly inhibited cell migration, tumor growth in bone and bone metastasis. Taken together, our results indicate that CCN3 enhances the migration of prostate cancer cells by increasing ICAM-1 expression through a signal transduction pathway that involves αvβ3 integrin, ILK, Akt and NF-κB. CCN3 thus represents a promising new target for treating prostate cancer.