title: Simvastatin, an HMG-CoA reductase inhibitor, exhibits anti-metastatic and anti-tumorigenic effects in endometrial cancer.
abstract: OBJECTIVE
  Our goal was to evaluate the effects of simvastatin on endometrial cancer cell lines and primary cultures of endometrial cancer cells.
  
  
  METHODS
  Cell proliferation in the ECC-1 and Ishikawa endometrial cancer cell lines and primary cultures of endometrial cancer cells was assessed by MTT assay. Apoptosis and cell cycle were detected by Annexin V assay and propidium iodide staining, respectively. Reactive oxygen species and cell adhesion were assessed using ELISA assays. Invasion was analyzed using a transwell invasion assay. Mitochondrial DNA damage was confirmed using qPCR. The effects of simvastatin on the AKT/mTOR and MAPK pathways were determined by Western blotting.
  
  
  RESULTS
  Simvastatin inhibited cell proliferation in a dose-dependent manner in both endometrial cancer cell lines and 5/8 primary cultures of endometrial cancer cells. Simvastatin treatment resulted in G1 cell cycle arrest, a reduction in the enzymatic activity of HMG-CoA, induction of apoptosis as well as DNA damage and cellular stress. Treatment with simvastatin resulted in inhibition of the MAPK pathway and exhibited differential effects on the AKT/mTOR pathway in the ECC-1 and Ishikawa cells. Minimal change in AKT phosphorylation was seen in both cell lines. An increase in phosphorylated S6 was seen in ECC-1 and a decrease was seen in Ishikawa. Treatment with simvastatin reduced cell adhesion and invasion (p<0.01) in both cell lines.
  
  
  CONCLUSIONS
  Simvastatin had significant anti-proliferative and anti-metastatic effects in endometrial cancer cells, possibly through modulation of the MAPK and AKT/mTOR pathways, suggesting that statins may be a promising treatment strategy for endometrial cancer.
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Monica N
authors.initials: MN
authors.lastname: Schointuch
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Timothy P
authors.initials: TP
authors.lastname: Gilliam
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Jessica E
authors.initials: JE
authors.lastname: Stine
authors.affiliation: ShanDong Tumor Hospital, Jinan University, Division of Gynecologic Oncology, Jinan 250117, PR China.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Han
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Zhou
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Paola A
authors.initials: PA
authors.lastname: Gehrig
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Kim
authors.affiliation: Division of Gynecologic Oncology, University of North Carolina, Chapel Hill, NC, USA; Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill, NC, USA. Electronic address: victoria_baejump@med.unc.edu.
authors.forename: Victoria L
authors.initials: VL
authors.lastname: Bae-Jump
mesh_terms: D017209:Apoptosis / Q000187:drug effects; D002448:Cell Adhesion / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000627:therapeutic use*; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis / Q000188:drug therapy; D019821:Simvastatin / Q000627:therapeutic use*; D014407:Tumor Cells, Cultured
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D019821:Simvastatin
keywords: AKT/mTOR pathway; Endometrial cancer; Invasion; MAPK pathway; Simvastatin; Statins