Simvastatin reduces the production of prothrombotic prostasomes in human prostate cancer cells.
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 pro-coagulant 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, whereas TF 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 cytometry. 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.
Department of Medical Sciences, Clinical Chemistry, Akademiska Hospital, Uppsala, Sweden. mikael.aberg@medsci.uu.se
Mikael
M
Aberg
Matilda
M
Johnell
Malin
M
Wickström
Anna
A
Widunder
Agneta
A
Siegbahn
D000924:Anticholesteremic Agents / Q000494:pharmacology*; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D005434:Flow Cytometry; D006801:Humans; D008297:Male; D010316:Particle Size; D011471:Prostatic Neoplasms / Q000150:complications / Q000378:metabolism* / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology*; D013925:Thromboplastin / Q000235:genetics / Q000378:metabolism*; D020246:Venous Thrombosis / Q000150:complications / Q000517:prevention & control*
D000924:Anticholesteremic Agents; D017077:Culture Media, Conditioned; D013925:Thromboplastin; D019821:Simvastatin