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

摘要: 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 proliferative activity cancer cells, especially those with TP53 mutations. Because mutations occur almost all ovarian high-grade serous carcinoma (HGSC), we determined whether suppressed tumor growth animal models cancer. Experimental Design: Two mouse were used. The first one was a genetically engineered model, mogp-TAg, which promoter oviduct glycoprotein-1 used drive expression SV40 T-antigen gynecologic tissues. These mice spontaneously developed tubal intraepithelial carcinomas (STICs), known as precursor lesions. second model xenograft human cells inoculated into immunocompromised mice. Mice both treated lovastatin, effects on monitored. molecular mechanisms underlying antitumor lovastatin also investigated. Results: Lovastatin significantly reduced development STICs mogp-TAg inhibited model. Knockdown prenylation enzymes mevalonate pathway recapitulated lovastatin-induced antiproliferative phenotype. Transcriptome analysis indicated that affected genes associated DNA replication, Rho/PLC signaling, glycolysis, cholesterol biosynthesis pathways, suggesting pleiotropic cells. Conclusions: above results suggest repurposing statin for may provide promising strategy prevent manage this devastating disease. Clin Cancer Res; 21(20); 4652–62. ©2015 AACR .