Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.
Mevalonate Pathway Antagonist Suppresses Formation of Serous Tubal Intraepithelial Carcinoma and Ovarian Carcinoma in Mouse Models.
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DOI：
10.1158/1078-0432.ccr-14-3368
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发表时间：
2015-10-15
期刊：
影响因子：
--
通讯作者：
Wang TL
中科院分区：
文献类型：
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作者：
Kobayashi Y;Kashima H;Wu RC;Jung JG;Kuan JC;Gu J;Xuan J;Sokoll L;Visvanathan K;Shih IeM;Wang TL
他汀类药物是最常用的处方药之一，因为它们在治疗高胆固醇血症中的疗效和低毒性。最近，他汀类药物已被报道抑制癌细胞的增殖活性，特别是那些与TP 53突变。由于TP 53突变发生在几乎所有的卵巢高级别浆液性癌中，我们确定他汀类药物是否抑制卵巢癌动物模型中的肿瘤生长。采用两种卵巢癌小鼠模型。第一种是利用输卵管糖蛋白-1启动子驱动SV 40 T抗原在妇科组织中表达的基因工程模型mogp-TAg。这些小鼠自发地发展浆液性输卵管上皮内癌（STIC），其被称为卵巢癌前体病变。第二个模型是异种移植肿瘤模型，其中将人卵巢癌细胞接种到免疫功能低下的小鼠中。两种模型中的小鼠均用洛伐他汀治疗，并监测对肿瘤生长的影响。本文还对洛伐他汀抗肿瘤作用的分子机制进行了初步探讨。洛伐他汀显著减少了mogp-TAg小鼠中STIC的发展，并抑制了小鼠异种移植模型中卵巢肿瘤的生长。在甲羟戊酸途径中异戊二烯化酶的敲低概括了洛伐他汀诱导的抗增殖表型。转录组分析表明，洛伐他汀影响与DNA复制，Rho/PLC信号，糖酵解和胆固醇生物合成途径相关的基因的表达，表明他汀类药物对肿瘤细胞具有多效性作用。上述结果表明，重新利用他汀类药物治疗卵巢癌可能为预防和管理这种毁灭性疾病提供一种有希望的策略。
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.