Wnt信号通路
基因敲除
抄写(语言学)
辅活化剂
连环素
细胞生物学
转录因子
MAPK/ERK通路
癌症研究
化学
P-糖蛋白
信号转导
连环蛋白
生物
多重耐药
抗药性
细胞培养
生物化学
遗传学
基因
哲学
语言学
作者
Zanxian Xia,Mingquan Guo,Han Liu,Luwei Jiang,Qiao-Xia Li,Jian Peng,Jia Li,Baoen Shan,Pinghui Feng,Hong Ma
出处
期刊:Current Cancer Drug Targets
[Bentham Science]
日期:2015-06-30
卷期号:15 (6): 519-532
被引量:16
标识
DOI:10.2174/1568009615666150506093643
摘要
Aberrant expression of the MDR1-encoded P-glycoprotein (P-gp) is often associated with clinical multi-drug resistance (MDR) leading to poor prognosis and failure of chemotherapy. However, the precise and cooperative molecular mechanism responsible for MDR1 transcription and expression in acquired MDR remains elusive. We, herein, demonstrate that Wnt/β-catenin signal pathway is constitutively activated in Doxorubicin-induced MDR cancer cells, in which nuclear β -catenin specifically interacts with the transcriptional coactivator CBP in a MEK(1/2)/ERK(1/2) signal-dependent manner. Specific knockdown of both β-catenin and CBP by RNAi-mediated depletion abrogates MDR1 transcription and expression resulting in a complete reversal of P-gp-dependent efflux function and restoration of sensitivity to the Doxorubincin-induced cytotoxicity. Moreover, following pharmacological disruption of CBP and β - catenin interaction through inhibition of the MEK(1/2)/ERK(1/2) signal by the specific inhibitor PD98059, MDR1 transcription and its encoded P-gp-dependent function are abolished. These findings conclude that the CBP/β-catenin complex is a core component of the MDR1 transcriptional "enhancesome".
科研通智能强力驱动
Strongly Powered by AbleSci AI