Rhamnetin and Cirsiliol Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition (EMT) by miR-34a-mediated Suppression of Notch-1 Expression in Non-small Cell Lung Cancer Cell Lines
Rhamnetin and Cirsiliol Induce Radiosensitization and Inhibition of Epithelial-Mesenchymal Transition (EMT) by miR-34a-mediated Suppression of Notch-1 Expression in Non-small Cell Lung Cancer Cell Lines
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DOI：
10.1074/jbc.m113.490482
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发表时间：
2013-09-20
影响因子：
4.8
通讯作者：
Youn, BuHyun
中科院分区：
文献类型：
--
作者：
Kang, JiHoon;Kim, EunGi;Youn, BuHyun
放射耐药是降低非小细胞肺癌（NSCLC）放疗效率的主要原因。为了了解非小细胞肺癌的辐射耐药机制，我们重点研究了辐射诱导的Notch-1信号通路，该通路通过调节细胞增殖参与关键的细胞命运决定。在这项研究中，我们研究了使用notch -1调节类黄酮化合物作为新型治疗药物来调节NCI-H1299和NCI-H460不同程度放射耐药的NSCLC细胞的放射敏感性。根据活性和药理学筛选结果，选择鼠李素和茜草醇作为notch -1调节放射增敏剂。鼠李素或茜草醇通过抑制辐射诱导的Notch-1表达来降低NSCLC细胞的增殖。事实上，鼠李素和千禧年醇以p53依赖的方式增加了肿瘤抑制microRNA miR-34a的表达，从而抑制了Notch-1的表达。因此，Notch-1表达降低通过显著下调核因子- κ B通路促进细胞凋亡，对NSCLC细胞具有放射增敏作用。在鼠李糖素和千禧年醇的存在下，辐照诱导的上皮-间质转化也明显减弱。此外，体内异种移植小鼠模型证实了我们在体外观察到的鼠李糖素和茜草醇的放射增敏和上皮-间质转化抑制作用。在这些小鼠中，与单独照射相比，照射与鼠李糖素或茜草醇联合治疗可显著减少肿瘤体积。综上所述，我们的研究结果提供了证据，证明鼠李素和茜草醇可以作为有希望的放射增敏剂，通过抑制辐射诱导的Notch-1信号通路（可能通过mir -34a介导的途径）来增强放射治疗疗效。
Radioresistance is a major cause of decreasing the efficiency of radiotherapy for non-small cell lung cancer (NSCLC). To understand the radioresistance mechanisms in NSCLC, we focused on the radiation-induced Notch-1 signaling pathway involved in critical cell fate decisions by modulating cell proliferation. In this study, we investigated the use of Notch-1-regulating flavonoid compounds as novel therapeutic drugs to regulate radiosensitivity in NSCLC cells, NCI-H1299 and NCI-H460, with different levels of radioresistance. Rhamnetin and cirsiliol were selected as candidate Notch-1-regulating radiosensitizers based on the results of assay screening for activity and pharmacological properties. Treatment with rhamnetin or cirsiliol reduced the proliferation of NSCLC cells through the suppression of radiation-induced Notch-1 expression. Indeed, rhamnetin and cirsiliol increased the expression of tumor-suppressive microRNA, miR-34a, in a p53-dependent manner, leading to inhibition of Notch-1 expression. Consequently, reduced Notch-1 expression promoted apoptosis through significant down-regulation of the nuclear factor-kappa B pathway, resulting in a radiosensitizing effect on NSCLC cells. Irradiation-induced epithelial-mesenchymal transition was also notably attenuated in the presence of rhamnetin and cirsiliol. Moreover, an in vivo xenograft mouse model confirmed the radiosensitizing and epithelial-mesenchymal transition inhibition effects of rhamnetin and cirsiliol we observed in vitro. In these mice, tumor volume was significantly reduced by combinational treatment with irradiation and rhamnetin or cirsiliol compared with irradiation alone. Taken together, our findings provided evidence that rhamnetin and cirsiliol can act as promising radiosensitizers that enhance the radiotherapeutic efficacy by inhibiting radiation-induced Notch-1 signaling associated with radioresistance possibly via miR-34a-mediated pathways.