Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models
| Autor: | Jinghua Gu, Jianhua Xuan, Jin Gyoung Jung, Ie Ming Shih, Hiroyasu Kashima, Kala Visvanathan, Tian Li Wang, Ren-Chin Wu, Yusuke Kobayashi, Jen Chun Kuan, Lori J. Sokoll |
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| Rok vydání: | 2015 |
| Předmět: |
DNA Replication
Cancer Research medicine.medical_specialty Statin Serous carcinoma medicine.drug_class Mevalonic Acid Antineoplastic Agents Biology Article Mice Ovarian tumor Cell Line Tumor Ovarian carcinoma Internal medicine medicine Animals Humans Lovastatin Cell Proliferation Ovarian Neoplasms Cancer Serous Tubal Intraepithelial Carcinoma medicine.disease Disease Models Animal Endocrinology Oncology Cancer research Female lipids (amino acids peptides and proteins) Tumor Suppressor Protein p53 Ovarian cancer Carcinoma in Situ Signal Transduction medicine.drug |
| Zdroj: | Clinical Cancer Research. 21:4652-4662 |
| ISSN: | 1557-3265 1078-0432 |
| DOI: | 10.1158/1078-0432.ccr-14-3368 |
| Popis: | 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. Clin Cancer Res; 21(20); 4652–62. ©2015 AACR. |
| Databáze: | OpenAIRE |
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