The differential effects of statins on the metastatic behaviour of prostate cancer

Abstract

Background: Although statins do not affect the incidence of prostate cancer (CaP), usage reduces the risk of clinical progression and mortality. Although statins are known to downregulate the mevalonate pathway, the mechanism by which statins reduce CaP progression is unknown.Methods:Bone marrow stroma (BMS) was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. PC-3 binding, invasion and colony formation within BMS was assessed by standardised in vitro co-culture assays in the presence of different statins.Results:Statins act directly on PC-3 cells with atorvastatin, mevastatin, simvastatin (1μM) and rosuvastatin (5μM), but not pravastatin, significantly reducing invasion towards BMS by an average of 66.68% (range 53.93-77.04%; P<0.05) and significantly reducing both number (76.2±8.29 vs 122.9±2.48; P<0.0055) and size (0.2±0.0058 mm 2 vs 0.27±0.012 mm 2; P=0.0019) of colonies formed within BMS. Statin-treated colonies displayed a more compact morphology containing cells of a more epithelial phenotype, indicative of a reduction in the migrational ability of PC-3 cells. Normal PC-3 phenotype and invasive ability was recovered by the addition of geranylgeranyl pyrophosphate (GGPP). Conclusion: Lipophilic statins reduce the migration and colony formation of PC-3 cells in human BMS by inhibiting GGPP production, reducing the formation and the spread of metastatic prostate colonies. © 2012 Cancer Research UK. All rights reserved.