title: A mitochondrial DNA mutation influences the apoptotic effect of statins on prostate cancer.
abstract: BACKGROUND
  Statins, 3-hydroxy-3 methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors, are currently the most widely used cholesterol-lowering drugs. Previous epidemiological studies have suggested that there may be be an association between statin use and decreased risk of prostate cancer progression. Both inherited and somatic mutations of the mitochondrial genome are linked to prostate cancer. The purpose of this study was to determine if mitochondrial DNA (mtDNA) background and hence mitochondrial biochemistry can modulate the efficiency of statin as an anti-prostate cancer agent.
  
  
  METHODS
  Cytoplasmic hybrid (cybrid) cell lines were constructed that contained a prostate cancer nucleus and either wild type or mutant mtDNA derived from a prostate cancer patient with the cytochrome oxidase subunit 1 gene mutation T6124C (Met74Thr). Multiple clones for each genotype were tested. After treating both wild type and mutant cells with increasing concentrations of simvastatin for 72 hr, cell proliferation and apoptosis were analyzed.
  
  
  RESULTS
  Simvastatin inhibited both wild type and mutant cell proliferation. However, cells with the T6124C mtDNA mutation were more resistant to drug treatment than the wild type cells. In addition, analysis of caspase 3 assays and multiple proteins involved in cellular apoptosis demonstrated that mutant cells were more resistant to simvastatin treatment-induced apoptosis than wild type control cells.
  
  
  CONCLUSIONS
  Simvastatin treatment induced apoptosis in human cybrid prostate cancer cells. The response to drug treatments was different depending on mitochondrial genotype. Therefore, the degree to which statins may affect prostate cancer progression may vary based on an individual's mtDNA background.
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Qian
authors.initials: Q
authors.lastname: Sun
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, Georgia.|Emory University Winship Cancer Institute, Atlanta, Georgia.
authors.forename: Rebecca S
authors.initials: RS
authors.lastname: Arnold
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: Carrie Q
authors.initials: CQ
authors.lastname: Sun
authors.affiliation: Department of Urology, Emory University School of Medicine, Atlanta, Georgia.|Emory University Winship Cancer Institute, Atlanta, Georgia.|The Atlanta VA Medical Center, Decatur, Georgia.|Emory University Winship Cancer Institute, Atlanta, Georgia.|Department of Pathology, Emory University School of Medicine, Atlanta, Georgia.|Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, Georgia.
authors.forename: John A
authors.initials: JA
authors.lastname: Petros
mesh_terms: D017209:Apoptosis / Q000187:drug effects* / Q000235:genetics*; D002453:Cell Cycle / Q000187:drug effects; D045744:Cell Line, Tumor; D004272:DNA, Mitochondrial / Q000235:genetics*; D018450:Disease Progression; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology; D019821:Simvastatin / Q000494:pharmacology* / Q000627:therapeutic use
chemical_list: D004272:DNA, Mitochondrial; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: apoptosis; mitochondria; prostate cancer; simvastatin