Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways
Camptothecin Induces Apoptosis in Cancer Cells via MicroRNA-125b-Mediated Mitochondrial Pathways
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DOI：
10.1124/mol.111.076794
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发表时间：
2012-04-01
影响因子：
3.6
通讯作者：
Chen, Yue-Qin
中科院分区：
文献类型：
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作者：
Zeng, Cheng-Wu;Zhang, Xing-Ju;Chen, Yue-Qin
喜树碱（Camptothecin，CPT）是一种治疗恶性肿瘤的有效化疗药物。CPT介导的癌细胞反应的机制尚未完全了解。微小RNA（microRNA，miRNA）在肿瘤的发生和药物敏感性中起重要作用。然而，喜树碱和miRNA之间的相互作用尚未被探索。在这项研究中，我们证实了miR-125 b在CPT诱导的癌细胞凋亡中下调，并且miR-125 b的异位表达部分恢复了细胞活力并抑制了CPT诱导的细胞凋亡。此外，我们证明CPT通过miR-125 b介导的线粒体途径通过靶向Bak 1，Mcl 1和p53的3 '-非翻译（UTR）区域诱导癌细胞凋亡。CPT处理后，Bak 1、Mcl 1和p53蛋白水平显著增加。值得注意的是，Bak 1、Mcl 1和p53的表达水平以时间依赖性方式增加，并且与miR-125 b表达呈负相关。值得注意的是，我们发现miR-125 b直接靶向CPT诱导的线粒体途径中多个基因的3 'UTR区域。此外，miR-125 b的大多数靶点是促凋亡基因，而一些靶点是抗凋亡基因。我们推测miR-125 b可能通过调节多个靶点介导化疗药物诱导细胞凋亡的活性。这是首次报道喜树碱通过miRNA介导的线粒体途径诱导癌细胞凋亡。这些结果表明，抑制miR-125 b可能是治疗癌症的一种新方法。
Camptothecin (CPT) is an effective chemotherapeutic agent for treatment of patients with cancer. The mechanisms underlying CPT-mediated responses in cancer cells are not fully understood. MicroRNA (miRNA) play important roles in tumorigenesis and drug sensitivity. However, the interaction between camptothecin and miRNA has not been previously explored. In this study, we verified that miR-125b was down-regulated in CPT-induced apoptosis in cancer cells and that ectopic expression of miR-125b partially restored cell viability and inhibited cell apoptosis that was induced by CPT. In addition, we demonstrated that CPT induced apoptosis in cancer cells by miR-125b-mediated mitochondrial pathways via targeting to the 3'-untranslated (UTR) regions of Bak1, Mcl1, and p53. A significant increase in Bak1, Mcl1, and p53 protein levels was detected in response to the treatments of CPT. It is noteworthy that the expression levels of Bak1, Mcl1, and p53 increased in a time-dependent manner and negatively correlated with miR-125b expression. It is noteworthy that we revealed that miR-125b directly targeted the 3'UTR regions of multiple genes in a CPT-induced mitochondrial pathway. In addition, most targets of miR-125b were proapoptotic genes, whereas some of the targets were antiapoptotic genes. We hypothesized that miR-125b may mediate the activity of chemotherapeutic agents to induce apoptosis by regulating multiple targets. This is the first report to show that camptothecin induces cancer cell apoptosis via miRNA-mediated mitochondrial pathways. The results suggest that suppression of miR-125b may be a novel approach for the treatment of cancer.