The proteoglycanase ADAMTS15 is an extracellular enzyme that targets versican. ADAMTS-15 is a putative tumour suppressor gene in breast and colon cancer. Its expression is also suppressed in prostate cancer (PrCa) cells by androgens. VCAN accumulation prevents adhesion and promotes migrationof PrCa cells, highlighting a possible tumour suppressive mechanism. We hypothesise that ADAMTS-15 is a tumour suppressor in PrCa. The aims of this study were: (1) to examine the expression and regulation of ADAMTS-15 in PrCa cells, (2) to determine the effect of ADAMTS-15 PrCa cell proliferation, migration and survival, and (3) to determine the localisation of ADAMTS-15 in PrCa patient biopsies. ADAMTS-15 and VCAN were expressed in the LNCaP (androgen-dependent) and PC-3 (castrate-resistant) cell lines. EGF (50 ng/ml) significantly up-regulated ADAMTS-15 (24h, P=<0.05) and IL-6 (50 ng/ml) or EGF (50 or 100 ng/ml) significantly down-regulated VCAN (24h, P=<0.001) in PC-3 cells. Monolayers of PC-3 cells treated with exogenous ADAMTS-15, or stably expressing ADAMTS-15 significantly decreased the rate of cell migration (6h, P=<0.05; 24h, P=<0.01). Stable expression of ADAMTS-15 in LNCaP and PC-3 cells significantly decreased cell proliferation (48h, P=<0.01). In patient biopsies ADAMTS-15 was predominantly localised to stroma in benign prostatic hyperplasia, and in both stromal and glandular epithelial in low and high grade PrCa. Our data suggests ADAMTS-15 inhibits PrCa cell proliferation and cell migration. To our knowledge, this is the first report of ADAMTS-15 localisation in PrCa specimens. Further studies are required to investigate the association of ADAMTS-15, versican throughout PrCa progression.