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Mevalonate pathway antagonist inhibits proliferation of serous tubal intraepithelial carcinoma and ovarian carcinoma in mouse models.


ABSTRACT: 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. Since *TP53* mutations occur in almost all of the ovarian high-grade serous carcinoma, we determined if statins suppressed tumor growth in animal models of ovarian cancer. Two ovarian cancer mouse models were employed. 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 develop 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 anti-tumor effects of lovastatin were also investigated. 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 anti-proliferative 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. The above results suggest that repurposing statin drugs for ovarian cancer may provide a promising strategy to prevent and manage this devastating disease. SKOV3 and OVCAR5 cells were treated with either 10uM Lovastatin or DMSO for 48 hours before harvested for gene expression array.

ORGANISM(S): Homo sapiens

SUBMITTER: Ie-Ming Shih 

PROVIDER: E-GEOD-68986 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

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

Kobayashi Yusuke Y   Kashima Hiroyasu H   Wu Ren-Chin RC   Jung Jin-Gyoung JG   Kuan Jen-Chun JC   Gu Jinghua J   Xuan Jianhua J   Sokoll Lori L   Visvanathan Kala K   Shih Ie-Ming IeM   Wang Tian-Li TL  

Clinical cancer research : an official journal of the American Association for Cancer Research 20150624 20


<h4>Purpose</h4>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.<h4>Experimental design</h4>Two ovarian cancer  ...[more]

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