Recombinant Dual-target MDM2/MDMX Inhibitor Reverses Doxorubicin Resistance through Activation of the TAB1/TAK1/p38 MAPK Pathway in Wild-type p53 Multidrug-resistant Breast Cancer Cells
Recombinant Dual-target MDM2/MDMX Inhibitor Reverses Doxorubicin Resistance through Activation of the TAB1/TAK1/p38 MAPK Pathway in Wild-type p53 Multidrug-resistant Breast Cancer Cells
复制标题
重组双靶点 MDM2/MDMX 抑制剂通过激活野生型 p53 多重耐药乳腺癌细胞中的 TAB1/TAK1/p38 MAPK 通路逆转阿霉素耐药性
DOI：
10.7150/jca.32765
复制
发表时间：
2020-01-01
影响因子：
3.9
通讯作者：
Geng, Qianqian
中科院分区：
文献类型：
--
作者：
Fan, Yangwei;Ma, Ke;Geng, Qianqian
化疗耐药是乳腺癌患者治疗的主要障碍，并极大地限制了一线化疗药物阿霉素(DOX)的疗效。本研究旨在探讨重组双靶点小鼠双分钟2(MDM2)和小鼠双分钟X(MDMX)抑制剂逆转BC对阿霉素耐药的可行性。两种DOX耐药的人乳腺癌细胞株都表现出多药耐药(MDR)表型。随后验证了双靶点MDM2/MDMX抑制剂逆转阿霉素耐药性的能力(逆转指数分别为9.15和13.92倍)。我们观察到MDM2/MDMX抑制剂与DOX联合应用可以抑制细胞增殖，促进细胞周期停滞，并诱导细胞凋亡。此外，它还能减少DOX耐药BC细胞中罗丹明123的外排，从而在BC裸鼠模型中发挥关键作用。联合用药组P-糖蛋白/多药耐药相关蛋白/CDC2/Bcl2表达降低，CyclinB1/Bax表达增加。小干扰RNA沉默和BC组织切片免疫组织化学染色显示，这些效应是由于转化生长因子β活化蛋白1结合蛋白1(TAB1)/Tak1/p38丝裂原活化蛋白激酶(MAPK)信号通路被激活所致。此外，在BC患者中，MDM2/MDMX的高表达与TAB1的弱表达呈正相关。因此，重组双靶点MDM2/MDMX抑制剂可通过激活Tab1/TAK1/p38 MAPK通路逆转野生型p53多药耐药BC对阿霉素的耐药性。
Chemotherapy resistance represents a major obstacle for the treatment of patients with breast cancer (BC) and greatly restricts the therapeutic effect of the first-line chemotherapeutic agent doxorubicin (DOX). The present study aimed to investigate the feasibility of the recombinant dual-target murine double minute 2 (MDM2) and murine double minute X (MDMX) inhibitor in reversing the DOX resistance of BC. Both DOX-resistant human breast carcinoma cell lines exhibited a multidrug resistance (MDR) phenotype. The ability of the dual-target MDM2/MDMX inhibitor in reversing doxorubicin resistance was subsequently verified, (9.15 and 13.92 - fold reversal indexes) respectively. We observed that the MDM2/MDMX inhibitor in combination with DOX could suppress proliferation, promote cell cycle arrest and induce apoptosis. In addition, it was capable of reducing rhodamine123 efflux in DOX-resistance BC cell lines and further played a key role in BC nude mice model. The groups that were treated with the combination of the drugs had decreased P-glycoprotein/multidrug resistance-associated protein/cdc 2/Bcl-2 expression and increased CyclinB1/Bax expression. These effects were caused due to activation of the transforming growth factor β-activated kinase 1 (TAK1)-binding protein 1 (TAB1)/TAK1/p38 mitogen-activated protein kinase (MAPK) signaling pathway, as shown by small interfering RNA (siRNA) silencing and immumohistochemical staining of BC tissue sections. Furthermore, high MDM2/MDMX expression was positively associated with weak TAB1 expression in BC patients. Therefore, the recombinant dual-target MDM2/MDMX inhibitor could reverse doxorubicin resistance via the activation of the TAB1/TAK1/p38 MAPK pathway in wild-type p53 multidrug-resistant BC.