Pygopus2 inhibits the efficacy of paclitaxel-induced apoptosis and induces multidrug resistance in human glioma cells.
Pygopus2 inhibits the efficacy of paclitaxel-induced apoptosis and induces multidrug resistance in human glioma cells.
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Pygopus2 抑制紫杉醇诱导的细胞凋亡的功效并诱导人神经胶质瘤细胞的多药耐药性。
DOI：
10.18632/oncotarget.15843
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发表时间：
2017-04-25
期刊：
影响因子：
--
通讯作者：
Tang J
中科院分区：
文献类型：
--
作者：
Zhou C;Cheng H;Qin W;Zhang Y;Xiong H;Yang J;Huang H;Wang Y;Chen XZ;Tang J
抗微管药物，如紫杉醇（PTX），广泛用于治疗许多癌症。然而，越来越多的证据表明，PTX耐药性，无论是内在的还是获得性的，经常发生在患者中，并导致治疗失败，导致癌症死亡率高。因此，有必要确定参与抗微管药物耐药性的基因或途径，以便将来成功治疗癌症。Pygopus 2（Pygo 2）含有锌协调的植物同源结构域（PHD）指状结构域，对于正常和恶性组织中的β-连环蛋白依赖性转录开关至关重要，并且在各种癌症（包括人脑胶质瘤）中过表达。在这项研究中，我们报告了Pygo 2的过表达抑制了PTX的疗效，并以两种不同的方式促成了细胞的多药耐药。首先，Pygo 2的过表达抑制了PTX诱导的B细胞淋巴瘤2（Bcl-2）的磷酸化，抑制了蛋白酶原-8/9的蛋白水解切割，并进一步抑制了半胱天冬酶-3的活化，这也抑制了JNK/SAPK通路的活化，最终抑制了细胞凋亡。其次，Pygo 2的过表达通过促进多药耐药1（MDR 1）启动子位点的转录，促进P-糖蛋白的表达，P-糖蛋白充当药物外排泵，从而加速紫杉醇的外排。
Anti-microtubule drugs, such as paclitaxel (PTX), are extensively used for the treatment of numerous cancers. However, growing evidence has shown that PTX resistance, either intrinsic or acquired, frequently occurs in patients and results in the failure of treatment, contributing to the high cancer mortality rate. Therefore, it is necessary to identify the genes or pathways involved in anti-microtubule drug resistance for future successful treatment of cancers. Pygopus2 (Pygo2), which contains a Zn-coordinated plant homeodomain (PHD) finger domain, is critical for β-catenin-dependent transcriptional switches in normal and malignant tissues and is over-expressed in various cancers, including human brain glioma. In this study, we report that over-expression of Pygo2 inhibited the efficacy of PTX and contributed to cell multidrug resistance in two different ways. First, over-expression of Pygo2 inhibited the PTX-induced phosphorylation of B-cell lymphoma 2 (Bcl-2), suppressing the proteolytic cleavage of procaspase-8/9 and further inhibiting the activation of caspase-3, which also inhibits the activation of the JNK/SAPK pathway, ultimately inhibiting cell apoptosis. Second, over-expression of Pygo2 facilitated the expression of P-glycoprotein, which acts as a drug efflux pump, by promoting the transcription of Multi-drug resistance 1 (MDR1) at the MDR1 promoter loci, resulting in acceleration of the efflux of PTX.