Suppression of NRF2/ARE by convallatoxin sensitises A549 cells to 5-FU-mediated apoptosis

被引：23
|
作者：
Lee, June [1 ]
Kang, Jong-Su [1 ]
Nam, Le Ba [1 ]
Yoo, Ok-Kyung [1 ]
Keum, Young-Sam [1 ]
机构：
[1] Dongguk Univ, Coll Pharm, 32 Dongguk Ro, Goyang 10326, Gyeonggi Do, South Korea
来源：
FREE RADICAL RESEARCH | 2018年 / 52卷 / 11-12期
基金：
新加坡国家研究基金会;
关键词：
5-Fluorouracil (5-FU); antioxidant response element (ARE); convallatoxin; NRF2; KEAP1-NRF2; PATHWAY; BETA-TRCP; CANCER;
D O I：
10.1080/10715762.2018.1489132
中图分类号：
Q5 [生物化学]; Q7 [分子生物学];
学科分类号：
071010 ; 081704 ;
摘要：
NF-E2-related factor 2 (NRF2) regulates transcription of phase II cytoprotective enzymes to protect normal cells against oxidative stress. However, a high level of NRF2 offers a growth advantage, chemoresistance, and radioresistance in cancer. In the present study, we have identified convallatoxin as a novel inhibitor of NRF2/ARE. Suppression of NRF2 by convallatoxin was not transcriptionally mediated, but regulated at the level of proteolysis. Convallatoxin activated GSK-3 beta and suppression of NRF2 by convallatoxin required the Neh6 domain. Convallatoxin sensitised A549 cells to 5-fluorouracil-mediated cell death by promoting apoptosis. Together, our results provide evidence that convallatoxin might be useful as a chemotherapeutic adjuvant due to its ability to suppress NRF2/ARE.
引用
收藏
页码：1416 / 1423
页数：8
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