Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models

Clin Cancer Res. 2015 Oct 15;21(20):4652-62. doi: 10.1158/1078-0432.CCR-14-3368. Epub 2015 Jun 24.


Purpose: 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.

Experimental design: 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology*
  • Carcinoma in Situ / drug therapy*
  • Carcinoma in Situ / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • DNA Replication / drug effects
  • Disease Models, Animal
  • Female
  • Humans
  • Lovastatin / pharmacology
  • Mevalonic Acid / antagonists & inhibitors*
  • Mice
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / metabolism
  • Signal Transduction / drug effects*
  • Tumor Suppressor Protein p53 / metabolism


  • Antineoplastic Agents
  • TP53 protein, human
  • Tumor Suppressor Protein p53
  • Lovastatin
  • Mevalonic Acid