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

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

Author information

1
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.
2
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.
3
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.
4
Department of Electrical and Computer Engineering, Virginia Polytechnic Institute and State University, Blacksburg, Virginia.
5
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.
6
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.
7
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.

Abstract

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.

PMID:
26109099
PMCID:
PMC4609247
DOI:
10.1158/1078-0432.CCR-14-3368
[Indexed for MEDLINE]
Free PMC Article

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