Twist1-Mediated Adriamycin-Induced Epithelial-Mesenchymal Transition Relates to Multidrug Resistance and Invasive Potential in Breast Cancer Cells
Twist1-Mediated Adriamycin-Induced Epithelial-Mesenchymal Transition Relates to Multidrug Resistance and Invasive Potential in Breast Cancer Cells
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Twist1介导的阿霉素诱导的上皮-间质转化与乳腺癌细胞的多药耐药性和侵袭潜力相关
DOI：
10.1158/1078-0432.ccr-08-2372
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发表时间：
2009-04-15
影响因子：
11.5
通讯作者：
Xu, Zu-De
中科院分区：
文献类型：
--
作者：
Li, Qing-Quan;Xu, Jing-Da;Xu, Zu-De
目的：在临床情况下，化疗药物除了具有治疗作用外，还会增强所治疗癌症的恶性程度。最近，上皮 - 间质转化（EMT）在肿瘤进展的研究中受到关注。我们旨在测试阿霉素短暂治疗是否会在癌细胞中同时诱导EMT和细胞凋亡，阐明为何同一类型的细胞对阿霉素治疗有不同反应（即细胞凋亡、EMT），并阐明EMT的主要调节因子Twist1在此过程中的作用。
实验设计：在非同步化的MCF7细胞或在不同阶段同步化的细胞中，在体外和体内检测阿霉素或/和Twist1小干扰RNA处理后的细胞凋亡、EMT以及并发事件[多药耐药（MDR）和肿瘤侵袭]。通过免疫印迹和免疫沉淀分别检测阿霉素诱导的Twist1表达以及Twist1与p53 - Mdm2的相互作用。
结果：我们在体外表明，阿霉素以细胞周期依赖的方式同时诱导EMT和细胞凋亡。只有经历EMT的细胞显示出增强的侵袭和多药耐药性。Twist1缺失完全阻断了间质转化，部分逆转了多药耐药性，并极大地消除了阿霉素诱导的侵袭。此外，我们在体内证实Twist1 RNA干扰提高了阿霉素对乳腺癌的疗效。进一步地，阿霉素处理细胞中Twist1的减少促进了p53依赖的p21诱导，并破坏了p53与Mdm2的关联。
结论：我们的研究显示了不同阶段细胞对阿霉素治疗的不同反应，提示了EMT在调节多药耐药和侵袭方面未被认识的作用，并显示了Twist1 RNA干扰在基于阿霉素的乳腺癌化疗中的疗效。
Purpose: Besides its therapeutic effects, chemotherapeutic agents also enhance the malignancy of treated cancers in clinical situations. Recently, epithelia I-mesenchymal transition (EMT) has attracted attention in studies of tumor progression. We aimed to test whether transient Adriamycin treatment induces EMT and apoptosis simultaneously in cancer cells, clarify why the same type of cells responds differentially (i.e., apoptosis, EMT) to Adriamycin treatment, and elucidate the role of Twist1, the master regulator of EMT, in this process.Experimental Design: In unsynchronized MCF7 cells or cells synchronized at different phases, apoptosis, EMT, and concurrent events [multidrug resistance (MDR) and tumor invasion] after Adriamycin or/and Twist1 small interfering RNA treatment were examined in vitro and in vivo. The Adriamycin-induced Twist1 expression and the interaction of Twist1 with p53-Mdm2 were examined by immunoblotting and immunoprecipitation, respectively.Results: We showed in vitro that Adriamycin induced EMT and apoptosis simultaneously in a cell cycle-dependent manner. Only the cells undergoing EMT displayed enhanced invasion and MDR. Twist1 depletion completely blocked the mesenchymal transformation, partially reversed MDR, and greatly abolished invasion induced by Adriamycin. Also, we confirmed in vivo that Twist1 RNA interference improved the efficacy of Adriamycin for breast cancers. Further, Twist1 reduction in Adriamycin-treated cells promoted p53-dependent p21 induction and disrupted the association of p53 with Mdm2.Conclusions: Our studies show the diverse responses to Adriamycin treatment in cells at different phases, suggest an unrecognized role of EMT in regulating MDR and invasion, and show the efficacy of Twist1 RNA interference in Adriamycin-based chemotherapies for breast cancer.