HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET
HDACI regulates the PI3K/Akt signaling pathway to reverse MCF-7/PTX resistance by inhibiting SET
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HDACI 通过抑制 SET 调节 PI3K/Akt 信号通路逆转 MCF-7/PTX 耐药
DOI：
10.1039/c6ra06423j
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发表时间：
2016-05
期刊：
影响因子：
3.9
通讯作者：
Chen Siying
中科院分区：
文献类型：
--
作者：
Zhang Weipeng;Zheng Xiaowei;Meng Ti;You Haisheng;Dong Yalin;Xing Jianfeng;Chen Siying
化疗耐药的发生极大地制约了抗肿瘤药物的疗效，因此迫切需要新的药物来消除耐药表型。在这项研究中，我们研究了患者SE翻译(SET)在人乳腺癌紫杉醇耐药细胞系(MCF-7/PTX)中的作用以及新的合成组蛋白去乙酰化酶抑制剂FA18的逆转机制。检测MCF-7/PTX细胞中SET、蛋白磷酸酶2A(PP2A)、磷脂酰肌醇3-激酶(PI3K)/蛋白激酶B(Akt)信号通路及下游线粒体凋亡通路的表达。为探讨SET在诱导耐药中的作用，应用SET拮抗剂OP449下调MCF-7/PTX细胞中SET的表达，观察SET对MCF-7/PTX细胞存活率、细胞凋亡率及通路相关因素的影响。此外，还研究了FA18的体内外逆转作用及其机制。我们发现在MCF-7/PTX细胞中SET和PI3K/Akt信号通路被激活。OP449下调SET使MCF-7/PTX细胞对紫杉醇(PTX)增敏，并诱导细胞凋亡。此外，SET诱导的PTX抗性与PI3K/Akt信号通路的激活和线粒体凋亡通路的抑制有关。FA18可显著降低MCF-7/PTX细胞SET的mRNA和蛋白水平。此外，FA18通过抑制PI3K/Akt信号通路和激活线粒体凋亡通路，显著抑制SET介导的抗性。此外，FA18在体内和体外均通过PI3K/Akt信号通路显著降低SET水平。这些结果提示，SET的过表达与MCF-7/PTX细胞的耐药性有关。FA18可能通过抑制SET/PI3K/Akt信号通路逆转这种耐药性。
The occurrence of chemoresistance greatly restricts the efficacy of antitumor drugs, and so novel agents are urgently needed to abrogate resistant phenotypes. In this study we investigated the role of patient SE translation (SET) in the human breast cancer paclitaxel-resistant cell line (MCF-7/PTX) and the underlying reversal mechanism of FA18, a new synthetic histone deacetylase inhibitor. The expressions of SET, protein phosphatase 2A (PP2A), and factors related to the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway and downstream mitochondrial apoptosis pathways were determined in MCF-7/PTX cells. In order to explore the role of SET in inducing drug resistance, a SET antagonist OP449 was used to down-regulate SET in MCF-7/PTX cells, and the cell viability, cell apoptosis, and pathway-related factors were assessed. Furthermore, the reversal effects of FA18 and its underlying mechanisms were investigated in vitro and in vivo. We found that SET and the PI3K/Akt signaling pathway were activated in MCF-7/PTX cells. The down-regulation of SET by OP449 significantly sensitized MCF-7/PTX cells to paclitaxel (PTX) and induced cell apoptosis. In addition, SET-induced PTX resistance was associated with activation of the PI3K/Akt signaling pathway and inhibition of mitochondrial apoptosis pathways. FA18 significantly reduced the mRNA and protein levels of SET in MCF-7/PTX cells. Furthermore, FA18 significantly inhibited SET-mediated resistance by attenuating the PI3K/Akt signaling pathway and activating mitochondrial apoptosis pathways. Additionally, FA18 significantly reduced the SET level via the PI3K/Akt signaling pathway both in vitro and in vivo. These results suggest that the overexpression of SET is associated with drug resistance in MCF-7/PTX cells. FA18 reversed this drug resistance, possibly via suppression of the SET/PI3K/Akt signaling pathway.
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影响因子：
3.8
作者：
S. O. Kim;B. Choi;I. Choi;J. Cheong;Gi-Young Kim;T. Kwon;N. Kim;Yung-Hyun Choi
通讯作者：
S. O. Kim;B. Choi;I. Choi;J. Cheong;Gi-Young Kim;T. Kwon;N. Kim;Yung-Hyun Choi
影响因子：
2.9
作者：
Shanghua Yin;C. Zeng;Malathi Hari;F. Cabral
通讯作者：
Shanghua Yin;C. Zeng;Malathi Hari;F. Cabral
DOI：
10.1158/1078-0432.ccr-13-2575
发表时间：
2014-04-15
期刊：
Clinical cancer research : an official journal of the American Association for Cancer Research
影响因子：
--
作者：
Agarwal A;MacKenzie RJ;Pippa R;Eide CA;Oddo J;Tyner JW;Sears R;Vitek MP;Odero MD;Christensen DJ;Druker BJ
通讯作者：
Druker BJ
PP2A抑制剂SET癌蛋白的过度表达与人类非小细胞肺癌的肿瘤进展和不良预后相关
影响因子：
--
作者：
Liu H;Gu Y;Wang H;Yin J;Zheng G;Zhang Z;Lu M;Wang C;He Z
通讯作者：
He Z
影响因子：
5.4
作者：
Cristóbal I;González-Alonso P;Daoud L;Solano E;Torrejón B;Manso R;Madoz-Gúrpide J;Rojo F;García-Foncillas J
通讯作者：
García-Foncillas J