Selective Enhancing Effect of Early Mitotic Inhibitor 1 (Emi1) Depletion on the Sensitivity of Doxorubicin or X-ray Treatment in Human Cancer Cells
Selective Enhancing Effect of Early Mitotic Inhibitor 1 (Emi1) Depletion on the Sensitivity of Doxorubicin or X-ray Treatment in Human Cancer Cells
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DOI：
10.1074/jbc.m112.446351
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发表时间：
2013-06-14
影响因子：
4.8
通讯作者：
Kudo, Yasusei
中科院分区：
文献类型：
--
作者：
Shimizu, Natsumi;Nakajima, Nakako Izumi;Kudo, Yasusei
除手术外，化疗和放疗已被证明对许多不同类型的癌症有效，但在这些治疗方法中，对正常组织的有效性是不可避免的。为了避免副作用，有选择地提高这些治疗方法在癌症组织中的有效性是很重要的。早期有丝分裂抑制因子1(Emi1)具有抑制细胞周期相关蛋白泛素化的后期促进复合体/环体泛素连接酶复合体的功能。最近的研究表明，Emi1基因被敲除后，通过后期促进复合体/环体的激活下调了Ginin的表达，从而阻止了从S到G(2)期的转变。目前常用的抗癌药物主要是靶向DNA合成干扰细胞快速分裂的药物。由于Emi1的缺失干扰了癌细胞中DNA合成的完成，我们认为Emi1的敲除可能会增强抗癌药物的敏感性。在此，我们证实了Emi1siRNA在几个癌细胞系中诱导多倍体以阻止从S向G(2)期的转变。然后，我们用阿霉素处理Emi1耗竭的细胞。有趣的是，在Emi1 siRNA处理的癌细胞中，观察到阿霉素处理后细胞凋亡率增加。此外，Emi1的耗尽增强了癌细胞对X射线照射的敏感性。重要的是，在这些联合治疗中没有观察到Emi1基因敲除在正常细胞中的协同作用。这些结果表明，Emi1 siRNA可以作为一种有用的工具来增强癌细胞对抗癌药物和辐射的敏感性。
Chemotherapy and radiation in addition to surgery has proven useful in a number of different cancer types, but the effectiveness in normal tissue cannot be avoided in these therapies. To improve the effectiveness of these therapies selectively in cancer tissue is important for avoiding side effects. Early mitotic inhibitor 1 (Emi1) is known to have the function to inhibit anaphase-promoting complex/cyclosome ubiquitin ligase complex, which ubiquitylates the cell cycle-related proteins. It recently has been shown that Emi1 knockdown prevents transition from S to G(2) phase by down-regulating geminin via anaphase-promoting complex/cyclosome activation. At present, anticancer drugs for targeting DNA synthesis to interfere with rapidly dividing cells commonly are used. As Emi1 depletion interferes with completion of DNA synthesis in cancer cells, we thought that Emi1 knockdown might enhance the sensitivity for anticancer agents. Here, we confirmed that Emi1 siRNA induced polyploidy for preventing transition from S to G(2) phase in several cancer cell lines. Then, we treated Emi1 depleted cells with doxorubicin. Interestingly, increased apoptotic cells were observed after doxorubicin treatment in Emi1 siRNA-treated cancer cells. In addition, Emi1 depletion enhanced the sensitivity of x-ray irradiation in cancer cells. Importantly, synergistic effect of Emi1 knockdown in these combination therapies was not observed in normal cells. These results suggest that Emi1 siRNA can be a useful tool for enhancing of sensitivity of cancer cells to anticancer reagents and radiation.