Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer
Truncated Bid Regulates Cisplatin Response via Activation of Mitochondrial Apoptosis Pathway in Ovarian Cancer
复制标题
截短的 Bid 通过激活卵巢癌线粒体凋亡途径调节顺铂反应
DOI：
10.1089/hum.2019.206
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发表时间：
2020-03-03
影响因子：
4.2
通讯作者：
Gao, Qing-Lei
中科院分区：
文献类型：
--
作者：
Dai, Yun;Zhao, Xue-Jiao;Gao, Qing-Lei
常规化疗的难治性是晚期卵巢癌（OC）治疗的主要挑战。越来越多的证据表明，线粒体启动与各种癌症中的顺铂反应相关。值得注意的是，Bim和BID是两种促细胞凋亡的仅含BH 3的蛋白质，被认为是OC中线粒体启动的最有效诱导剂。在这项研究中，我们构建了两个肿瘤特异性溶瘤腺病毒（Ads）的编码Bim（Ad-Bim）或截短的投标（Ad-tBid），分别，并在9 OC细胞系进行功能获得性测定。Ad-tBid具有显著的抗肿瘤效果。此外，Ad-tBid预处理，线粒体致敏细胞显示更敏感的顺铂在体外和离体。我们还发现，Ad-tBid诱导线粒体凋亡的Bak-dependent的方式。此外，联合顺铂加Ad-tBid治疗显着抑制皮下异种移植肿瘤模型中的肿瘤生长。在携带腹膜弥漫性OC的小鼠中，腹腔内给予Ad-tBID可增强顺铂的抗肿瘤作用。我们的研究结果表明，Ad-tBid增强顺铂在OC细胞中的反应，通过顺铂和Ad-tBid的组合建立晚期OC的潜在治疗。
Refractoriness to conventional chemotherapy is a major challenge in the treatment of advanced ovarian cancer (OC). There is increasing evidence that mitochondrial priming correlates with cisplatin response in various cancers. Notably, Bim and Bid, two of the proapoptotic BH3-only proteins, are recognized as the most effective inducers of mitochondrial priming in OC. In this study, we constructed two tumor-specific oncolytic adenoviruses (Ads) coding for Bim (Ad-Bim) or truncated Bid (Ad-tBid), respectively, and performed gain-of-function assays in nine OC cell lines. Ad-tBid exhibited significant antitumor efficacy than the controls. On addition of Ad-tBid pretreatment, mito-primed cells displayed more sensitivity to cisplatin both in vitro and ex vivo. We also found that Ad-tBid induced mitochondrial apoptosis in a Bak-dependent manner. Furthermore, a combined cisplatin plus Ad-tBid therapy markedly inhibited tumor growth in a subcutaneous xenotransplanted tumor model. In mice bearing peritoneal disseminated OC, intraperitoneal administration of Ad-tBid potentiated the antitumor effect of cisplatin. Our findings suggest that Ad-tBid enhances cisplatin response in OC cells, establishing the potential treatment of advanced OC via a combination of cisplatin and Ad-tBid.