title: Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.
abstract: OBJECTIVE
  Statins are among the most frequently prescribed drugs because of their efficacy and low toxicity in treating hypercholesterolemia. Recently, statins have been reported to inhibit the proliferative activity of cancer cells, especially those with TP53 mutations. Because TP53 mutations occur in almost all ovarian high-grade serous carcinoma (HGSC), we determined whether statins suppressed tumor growth in animal models of ovarian cancer.
  
  
  METHODS
  Two ovarian cancer mouse models were used. The first one was a genetically engineered model, mogp-TAg, in which the promoter of oviduct glycoprotein-1 was used to drive the expression of SV40 T-antigen in gynecologic tissues. These mice spontaneously developed serous tubal intraepithelial carcinomas (STICs), which are known as ovarian cancer precursor lesions. The second model was a xenograft tumor model in which human ovarian cancer cells were inoculated into immunocompromised mice. Mice in both models were treated with lovastatin, and effects on tumor growth were monitored. The molecular mechanisms underlying the antitumor effects of lovastatin were also investigated.
  
  
  RESULTS
  Lovastatin significantly reduced the development of STICs in mogp-TAg mice and inhibited ovarian tumor growth in the mouse xenograft model. Knockdown of prenylation enzymes in the mevalonate pathway recapitulated the lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that lovastatin affected the expression of genes associated with DNA replication, Rho/PLC signaling, glycolysis, and cholesterol biosynthesis pathways, suggesting that statins have pleiotropic effects on tumor cells.
  
  
  CONCLUSIONS
  The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease.
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Obstetrics and Gynecology, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Kobayashi
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Hiroyasu
authors.initials: H
authors.lastname: Kashima
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Pathology, Chang Gung Memorial Hospital and Chang Gung University, Taoyuan, Taiwan.
authors.forename: Ren-Chin
authors.initials: RC
authors.lastname: Wu
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jin-Gyoung
authors.initials: JG
authors.lastname: Jung
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Jen-Chun
authors.initials: JC
authors.lastname: Kuan
authors.affiliation: Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
authors.forename: Jinghua
authors.initials: J
authors.lastname: Gu
authors.affiliation: Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
authors.forename: Jianhua
authors.initials: J
authors.lastname: Xuan
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Lori
authors.initials: L
authors.lastname: Sokoll
authors.affiliation: The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Epidemiology, School of Public Health, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Kala
authors.initials: K
authors.lastname: Visvanathan
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Gynecology/Obstetrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland.
authors.forename: Ie-Ming
authors.initials: IeM
authors.lastname: Shih
authors.affiliation: Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland. The Sidney Kimmel Comprehensive Cancer Center, School of Medicine, Johns Hopkins University, Baltimore, Maryland. Department of Gynecology/Obstetrics, School of Medicine, Johns Hopkins University, Baltimore, Maryland. tlw@jhmi.edu.
authors.forename: Tian-Li
authors.initials: TL
authors.lastname: Wang
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D002278:Carcinoma in Situ / Q000188:drug therapy* / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004261:DNA Replication / Q000187:drug effects; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D008148:Lovastatin / Q000494:pharmacology; D008798:Mevalonic Acid / Q000037:antagonists & inhibitors*; D051379:Mice; D010051:Ovarian Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; D008148:Lovastatin; D008798:Mevalonic Acid