Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells

Mikael Åberg; Matilda Johnell; Malin Wickström; Anna Widunder; Agneta Siegbahn

doi:10.1160/TH08-03-0173

Thrombosis and Haemostasis, Inhaltsverzeichnis

Thromb Haemost 2008; 100(04): 655-662
DOI: 10.1160/TH08-03-0173

Cellular Proteolysis and Oncology

Schattauer GmbH

Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells

Mikael Åberg

¹Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, Uppsala, Sweden

,

Matilda Johnell

¹Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, Uppsala, Sweden

,

Malin Wickström

¹Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, Uppsala, Sweden

,

Anna Widunder

¹Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, Uppsala, Sweden

,

Agneta Siegbahn

¹Department of Medical Sciences, Clinical Chemistry and Pharmacology, Akademiska Hospital, Uppsala, Sweden

› Institutsangaben

Abstract

Summary

Cancer confers a prothrombotic state and statins are associated with a lowered risk for prostate cancer in vivo by unknown mechanisms. Prostate cancer cells release tissue factor (TF)-bearing, cholesterol-rich prostasomes which are procoagulant in vitro and a possible source for the blood-borne TF found in prostate cancer patients. We investigated the effect of cholesterol depletion on the production of prostasomes and on the TF activity in the conditioned medium of simvastatin-treated PC3 cells. Human PC3 prostate cancer cells were treated with high and low concentrations of simvastatin for different time periods. Caspase-3 was detected with the Array Scan microscope, where-asTF mRNA and protein were analyzed by TaqMan and flow cytometry. TF activity was assessed by measuring the cleavage of a chromogenic thrombin substrate. Prostasomes were isolated by repeated centrifugations and detected and quantified by flow cy tometry. A micromolar dose of simvastatin caused reduction of TF expression and induction of apoptosis in the PC3 cells. The levels of TF on the prostasomes were also decreased but the TF activity in the conditioned medium of the simvastatin-treated PC3 cells was increased due to apoptosis-dependent release of prostasomes. Treatment with a nanomolar dose of simvastatin did not induce apoptosis or alter the expression of TF but instead decreased the production and release of the prostasomes. The TF activity was reduced in parity with the decline in prostasome release. In conclusion, in prostate cancer, a nanomolar dose of simvastatin may have an anti-thrombotic effect due to decreased levels of circulating TF-bearing prostasomes.

Keywords

Apoptosis - deep vein thrombosis - malignancy - microparticles - tissue factor

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Referenzen

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