title: Oxysterols synergize with statins by inhibiting SREBP-2 in ovarian cancer cells.
abstract: OBJECTIVE
  Determine mechanisms responsible for enhanced statin efficacy in a novel statin combination we name STOX (STatin-OXysterol).
  
  
  METHODS
  Ovarian cancer cell lines were treated with combinations of statins and oxysterols. Cell viability was determined by a modified MTT assay. Apoptosis was evaluated by immunoblotting of PARP and DAPI-mediated visualization of apoptotic nuclei. STOX effects on the expression of genes of the mevalonate pathway were assessed by real-time qPCR and immunoblotting. siRNA-mediated gene silencing was used to test the involvement of oxysterol-mediated repression of SREBP-2 in STOX synergy. The impact of statin-mediated inhibition of protein prenylation and on cholesterol homeostasis was evaluated.
  
  
  RESULTS
  Oxysterols dramatically enhance cytotoxicity of statins in ovarian cancer cells through increased apoptosis. Decreased expression of SREBP-2 down-regulates the mevalonate pathway and prevents the active statin-induced sterol feedback, enhancing statin toxicity. Comparison of two ovarian cancer cell lines reveals two distinct mechanisms of statin induced toxicity, namely, dependence on protein geranylgeranylation and/or perturbation of cellular cholesterol levels.
  
  
  CONCLUSIONS
  We provide evidence of statins' mechanisms of cytotoxicity in different ovarian cancer cells and discovered a new approach to significantly enhance the anti-tumor activity of statins. These observations provide a potential new path to improve statins as a treatment against ovarian cancer with obtainable dosages.
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
authors.forename: Cinzia
authors.initials: C
authors.lastname: Casella
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
authors.forename: Daniel H
authors.initials: DH
authors.lastname: Miller
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA.
authors.forename: Kerry
authors.initials: K
authors.lastname: Lynch
authors.affiliation: Department of Molecular Biology, Cell Biology, and Biochemistry, Brown University, Providence, RI 02903, USA; Center for Computational Molecular Biology, Brown University, 151 Waterman St., Providence, RI 02912, USA; Center for Genomics and Proteomics, Brown University, 70 Ship St., Providence, RI 02903, USA.
authors.forename: Alexander S
authors.initials: AS
authors.lastname: Brodsky
mesh_terms: D017209:Apoptosis / Q000187:drug effects*; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004357:Drug Synergism; D004359:Drug Therapy, Combination; D005260:Female; D006801:Humans; D006888:Hydroxycholesterols / Q000494:pharmacology*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology*; D009375:Neoplasms, Glandular and Epithelial; D010051:Ovarian Neoplasms; D015398:Signal Transduction; D019821:Simvastatin / Q000494:pharmacology*; D051782:Sterol Regulatory Element Binding Protein 2 / Q000037:antagonists & inhibitors*
chemical_list: D006888:Hydroxycholesterols; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; C007997:25-hydroxycholesterol; D019821:Simvastatin
keywords: Cholesterol; Ovarian cancer; SREBPs; Statins