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Simvastatin inducing PC3 prostate cancer cell necrosis mediated by calcineurin and mitochondrial dysfunction
- Source :
- Journal of Bioenergetics and Biomembranes. 40:307-314
- Publication Year :
- 2008
- Publisher :
- Springer Science and Business Media LLC, 2008.
-
Abstract
- In the present study we analyzed the mechanisms of simvastatin toxicity for the PC3 human prostate cancer cell line. At 10 microM, simvastatin induced principally apoptosis, which was prevented by mevalonic acid but not by cyclosporin A, the inhibitor of calcineurin and mitochondrial permeability transition (MPT). At 60 microM, simvastatin induced the necrosis of PC3 cells insensitive to mevalonic acid. Cell necrosis was preceded by a threefold increase in cytosolic free Ca(2+) concentration and a significant decrease in both respiration rate and mitochondrial membrane potential. Both mitochondrial dysfunction and necrosis were sensitive to the compounds cyclosporin A and bongkrekic acid, as well as the calcineurin inhibitor FK506. We have concluded that simvastatin-induced PC3 cells apoptosis is dependent on 3-hydroxy-3-methylglutaryl coenzyme-A reductase inhibition and independent of MPT, whereas necrosis is dependent on mitochondrial dysfunction caused, at least in part, by calcineurin.
- Subjects :
- Male
Simvastatin
Programmed cell death
Necrosis
Physiology
Apoptosis
Mevalonic acid
Pharmacology
Biology
Mitochondrial Membrane Transport Proteins
chemistry.chemical_compound
Cell Line, Tumor
Cyclosporin a
polycyclic compounds
medicine
Humans
Cell Proliferation
Mitochondrial Permeability Transition Pore
Calcineurin
Prostatic Neoplasms
Cell Biology
Mitochondria
Cell biology
chemistry
Mitochondrial permeability transition pore
medicine.symptom
medicine.drug
Subjects
Details
- ISSN :
- 15736881 and 0145479X
- Volume :
- 40
- Database :
- OpenAIRE
- Journal :
- Journal of Bioenergetics and Biomembranes
- Accession number :
- edsair.doi.dedup.....85c9510d983b78733d25989ed133fcef