Abstract
INTRODUCTION AND OBJECTIVES: Exposure of cancer cells to statins result in the down-regulation of the mevalonate pathway by HMG-CoA reductase inhibition, inducing inhibition of a range of cellular functions such as membrane integrity, cell signalling, protein synthesis and cell cycle progression. Disruption of these processes may result in changes in the regulation of tumour initiation, growth and metastasis. Clinical studies have reported that statins do not effect the incidence of clinically significant prostate cancer but usage reduces the risk of progression and mortality (0.26; 95% CI 0.08–0.83 0.64; 95% CI 0.44–0.93). It is currently unclear how statins reduce the clinical progression of prostate cancer. Here we present in vitro data showing that statins act directly on the prostate epithelial cells, reducing their ability to invade through and form metastatic colonies in the bone marrow stroma (BMS). METHODS: BMS was isolated with ethical approval from consenting patients undergoing surgery for non-malignant disease. All statins were used at non-toxic doses as determined by colony forming assays (atorvastatin, mevastatin, simvastatin (1 M), rosuvastatin (5 M) & pravastatin (100 M)). Binding of statin treated PC-3GFP cells to BMS was assessed using a FLUOstar OPTIMA spectrometer. Invasion of statin treated PC-3 cells towards untreated BMS or 7 day statin pre-treated BMS was assessed using the FluoroBlok tumour co-culture cell invasion system. Colony formation was assessed by seeding statin treated PC-3 cells on to confluent BMS. Statins were refreshed daily for 8 days before fixing and staining with anti pancytokeratin, counting and measuring epithelial colonies. RESULTS: Statins do not affect the ability of PC-3 cells to bind to BMS. Pravastatin had no effect on PC-3 invasion or colony formation in BMS. Treating PC-3 cells with atorvastatin, mevastatin, simvastatin and rosuvastatin significantly reduced their ability to invade towards BMS as compared with untreated controls on average 66.68% (range 53.93%–77.04% p 0.05). These statins also significantly reduced the number (76.2 vs 118; p 0.05) and size (0.2mm vs 0.29mm; p 0.05) of colonies formed in BMS co-culture, with colonies displaying a more compact morphology indicative of a reduction in the ability to migrate through the BMS. CONCLUSIONS: Statins reduce the risk of prostate cancer progression by inhibiting the ability of malignant prostate epithelial cells to invade towards and through human BMS, reducing the formation and the spread of metastatic prostate colonies.
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