BACKGROUND The antimicrobial peptide, leucine-leucine-37 (LL-37), stimulates proliferation, angiogenesis, and cellular migration, inhibits apoptosis and is associated with inflammation. Since these functional processes are often exaggerated in cancer, the aim of the present study was to investigate the expression and role of LL-37 in prostate cancer (PCa) and establish its value as a therapeutic target. METHODS We evaluated the expression of LL-37 and the murine orthologue, cathelicidin-related antimicrobial peptide (CRAMP) in human and murine prostate tumors, respectively. Compared to normal/benign prostate tissue, both LL-37 and CRAMP were increasingly over-expressed with advancing grades of primary PCa and its metastasis in human tissues and in the transgenic adenocarcinoma mouse prostate (TRAMP) model, correspondingly. We subsequently knocked-down CRAMP in the highly tumorigenic TRAMP-C1 cell line via a RNA interference strategy to examine the importance of CRAMP on cellular proliferation, angiogenesis, invasion, apoptosis, activation of signaling pathways and tumor kinetics. RESULTS Abrogation of CRAMP expression led to decreased proliferation, invasion, type IV collagenase, and the amount of phosphorylated Erk1/2 and Akt signaling in vitro. These results were paralleled in vivo. Syngenic implantation of TRAMP-C1 cells subjected to CRAMP knock-down resulted in a decreased tumor incidence and size, and the down-regulation of pro-tumorigenic mechanisms. CONCLUSIONS CRAMP knock-down in a murine PCa model analogously demonstrated the tumorigenic contributions of LL-37 in PCa and its potential as a novel therapeutic target for the treatment of PCa and potentially, other cancers over-expressing the peptide. © 2010 Wiley-Liss, Inc.