Dissociation of E-cadherin/β-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells
Dissociation of E-cadherin/β-catenin complex by MG132 and bortezomib enhances CDDP induced cell death in oral cancer SCC-25 cells
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DOI：
10.1016/j.tiv.2015.07.008
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发表时间：
2015-12-01
影响因子：
3.2
通讯作者：
Huang, Hongzhang
中科院分区：
文献类型：
--
作者：
Lue, Lanhai;Liu, Xiqiang;Huang, Hongzhang
E-钙粘素/β-连环蛋白复合体在维持组织内环境平衡、调节细胞增殖、存活和凋亡等方面发挥着重要作用。为探讨E-钙粘蛋白/β-连环蛋白复合体的变化与细胞凋亡的关系，以人口腔鳞癌SCC-25细胞为研究对象，探讨E-钙粘连蛋白/β-连环蛋白复合体的解离是否是MG 132或硼替佐米诱导细胞凋亡的主要原因。我们发现，MG132或Bortezomib单独作用会导致细胞完整性和接触性显著丧失，抑制细胞的生长、存活和迁移，并导致细胞周期停滞，细胞内ROS产生。进一步的实验表明，MG132和硼替佐米单独或与顺式二氨基氯铂(CDDP)联合使用可显著减少集落形成。免疫荧光染色显示，经MG132或硼替佐米处理后，SCC-25细胞胞浆内有明显的β-连环蛋白积聚，细胞膜上几乎没有E-钙粘附素。Western印迹结果显示，MG132或Bortezomib可诱导泛素化蛋白的高积聚和凋亡相关蛋白caspase-3的激活。同时，MG132或硼替佐米与顺铂联合应用对SCC-25细胞有协同作用。然而，敲除β-连环蛋白可以减少MG132或Bortezomib诱导的细胞死亡。综上所述，我们的研究结果提示，E-钙粘蛋白/P-连环蛋白复合体的调控可能成为克服口腔癌多药耐药的一个有前途的治疗靶点。(C)2015爱思唯尔有限公司。保留所有权利。
E-cadherin/beta-catenin complex plays an important role in maintaining the homeostasis of tissues and regulating cell proliferation, survival and apoptosis. To address the relationships between the change of E-cadherin/P-catenin complex and cell apoptosis, human oral squamous carcinoma SCC-25 cells were used to investigate whether the dissociation of the E-cadherin/beta-catenin complex was the main reason of MG 132- or bortezomib-induced apoptosis. We found that MG132 or bortezomib alone induced remarkable loss of cell integrity and contact, inhibited cell growth, survival, migration and caused cell cycle arrest, intracellular ROS production. Further experiments showed that colony formations were significantly decreased by MG132 and bortezomib alone or plus cis-diaminedichloroplatinum (CDDP). Immunofluorescence staining showed that SCC-25 cells exhibited remarkable accumulations of beta-catenin in cytoplasm and few E-cadherin in cell membranes after MG132 or bortezomib treatment. Western blot results showed that MG132 or bortezomib induced high accumulation of ubiquitinated proteins and activation of apoptosis related protein caspase-3. Meanwhile, the combinational use of MG132 or bortezomib with CDDP led to synergistic effects on SCC-25 cells. However, knockdown of beta-catenin could decrease MG132 or bortezomib induced cell death. Taken together, our data suggest that the regulation of E-cadherin/P-catenin complex could be a promising therapeutic target to overcome the multidrug resistance of oral cancer. (C) 2015 Elsevier Ltd. All rights reserved.