title: Ovarian tumour growth is characterized by mevalonate pathway gene signature in an orthotopic, syngeneic model of epithelial ovarian cancer.
abstract: Epithelial ovarian cancer (EOC) is the most lethal gynecological cancer and often is not detected until late stages when cancer cells transcoelomically metastasize to the abdomen and typically become resistant to therapy resulting in very low survival rates. We utilize an orthotopic, syngeneic mouse model to study late stage disease and have discovered that the tumor cells within the abdominal ascites are irreversibly re-programmed, with an increased tumorigenicity and resistance to apoptosis. The goal of this study was to characterize the reprogramming that occurred in the aggressive ascites-derived cells (28-2 cells) compared to the original cell line used for tumor induction (ID8 cells). Microarray experiments showed that the majority of genes upregulated in the 28-2 cells belonged to the mevalonate pathway, which is involved in cholesterol biosynthesis, protein prenylation, and activation of small GTPases. Upregulation of mevalonate appeared to be associated with the acquisition of a p53 mutation in the ascites-derived cells. Treatment with simvastatin to inhibit HMG CoA reductase, the rate limiting enzyme of this pathway, induced apoptosis in the 28-2 cell line. Rescue experiments revealed that mevalonate, but not cholesterol, could inhibit the simvastatin-mediated effects. In vivo, daily intraperitoneal simvastatin treatment significantly regressed advanced stage disease and induced death of metastatic tumor cells. These data suggest that ovarian cancer cells become reprogrammed, with genetic mutations, and upregulation of the mevalonate pathway, which facilitates the development of advanced stage disease. The use of statins to inhibit HMGCR may provide novel therapeutic opportunities for the treatment of advanced stage EOC.
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: James B
authors.initials: JB
authors.lastname: Greenaway
authors.affiliation: Princess Margaret Genomics Centre, University Health Network, Toronto, ON, M5G 1L7, Canada.
authors.forename: Carl
authors.initials: C
authors.lastname: Virtanen
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: Kata
authors.initials: K
authors.lastname: Osz
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: Tamas
authors.initials: T
authors.lastname: Revay
authors.affiliation: Department of Ob/Gyn and Physiology and Pharmacology, Children's Health Research Institute, Western University, London, ON, N6A 5C1, Canada.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hardy
authors.affiliation: Department of Ob/Gyn and Oncology, Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, ON, N6A 4L6, Canada.
authors.forename: Trevor
authors.initials: T
authors.lastname: Shepherd
authors.affiliation: Department of Ob/Gyn and Oncology, Anatomy and Cell Biology, London Regional Cancer Program, Western University, London, ON, N6A 4L6, Canada.
authors.forename: Gabriel
authors.initials: G
authors.lastname: DiMattia
authors.affiliation: Department of Biomedical Sciences, University of Guelph, Guelph, ON, N1G 2W1, Canada.
authors.forename: Jim
authors.initials: J
authors.lastname: Petrik
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D000077216:Carcinoma, Ovarian Epithelial; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D005260:Female; D042822:Genomic Instability; D006801:Humans; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology; D008798:Mevalonic Acid / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D011106:Polyisoprenyl Phosphates / Q000494:pharmacology; D019821:Simvastatin / Q000494:pharmacology / Q000627:therapeutic use; D059016:Tumor Microenvironment
chemical_list: D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D011106:Polyisoprenyl Phosphates; D019821:Simvastatin; C002963:geranylgeranyl pyrophosphate; D008798:Mevalonic Acid
keywords: mevalonate pathway; ovarian cancer; p53; simvastatin