Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas.
Nutlin-3a: A Potential Therapeutic Opportunity for TP53 Wild-Type Ovarian Carcinomas.
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DOI：
10.1371/journal.pone.0135101
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发表时间：
2015
期刊：
影响因子：
3.7
通讯作者：
Wong KK
中科院分区：
文献类型：
--
作者：
Crane EK;Kwan SY;Izaguirre DI;Tsang YT;Mullany LK;Zu Z;Richards JS;Gershenson DM;Wong KK
上皮性卵巢癌是一种不同的分子和临床疾病，但所有亚型的标准治疗都是相同的。TP53突变代表上皮性卵巢癌组织学亚型的一个分歧点，并可能在表达野生型的亚型中提供治疗机会，包括大多数低级别卵巢浆液性癌、卵巢透明细胞癌和卵巢子宫内膜样癌，它们约占所有上皮性卵巢癌的25%。因此，我们试图研究Nutlin-3a作为一种治疗TP53野生型卵巢癌的化合物。Nutlin-3a是一种抑制MDM2、激活野生型p53并诱导细胞凋亡的治疗药物。用Nutlin-3a处理15株不同组织学亚型的卵巢癌细胞系，测定IC50值。Western Blot(WB)和实时定量聚合酶链式反应(qRT-PCR)分析了Nutlin-3a治疗后MDM2、p53和p21的表达。然后对来自15个细胞系的DNA进行测序，以检测外显子2-11包括内含子-外显子边界的TP53突变。对Nutlin-3a的反应取决于TP53突变状态。经qRT-PCR和WB检测，野生型TP53敏感细胞株mdm2和p21表达上调，突变型细胞株p21诱导表达降低或缺失。Annexin V检测显示，经Nutlin-3a处理的敏感细胞系发生了凋亡。因此，Nutlin-3a可能成为治疗表达野生型TP53的卵巢癌的潜在药物，值得进一步研究。
Epithelial ovarian cancer is a diverse molecular and clinical disease, yet standard treatment is the same for all subtypes. TP53 mutations represent a node of divergence in epithelial ovarian cancer histologic subtypes and may represent a therapeutic opportunity in subtypes expressing wild type, including most low-grade ovarian serous carcinomas, ovarian clear cell carcinomas and ovarian endometrioid carcinomas, which represent approximately 25% of all epithelial ovarian cancer. We therefore sought to investigate Nutlin-3a—a therapeutic which inhibits MDM2, activates wild-type p53, and induces apoptosis—as a therapeutic compound for TP53 wild-type ovarian carcinomas. Fifteen epithelial ovarian cancer cell lines of varying histologic subtypes were treated with Nutlin-3a with determination of IC50 values. Western Blot (WB) and quantitative real-time polymerase chain reaction (qRT-PCR) analyses quantified MDM2, p53, and p21 expression after Nutlin-3a treatment. DNA from 15 cell lines was then sequenced for TP53 mutations in exons 2-11 including intron-exon boundaries. Responses to Nutlin-3a were dependent upon TP53 mutation status. By qRT-PCR and WB, levels of MDM2 and p21 were upregulated in wild-type TP53 sensitive cell lines, and p21 induction was reduced or absent in mutant cell lines. Annexin V assays demonstrated apoptosis in sensitive cell lines treated with Nutlin-3a. Thus, Nutlin-3a could be a potential therapeutic agent for ovarian carcinomas expressing wild-type TP53 and warrants further investigation.