Brusatol overcomes chemoresistance through inhibition of protein translation.
Brusatol overcomes chemoresistance through inhibition of protein translation.
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DOI：
10.1002/mc.22609
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发表时间：
2017-05
影响因子：
4.6
通讯作者：
Zhang DD
中科院分区：
文献类型：
--
作者：
Harder B;Tian W;La Clair JJ;Tan AC;Ooi A;Chapman E;Zhang DD
当细胞暴露于外源物或处于氧化应激状态时，NRF2通路激活细胞生存反应。治疗性激活NRF2也可以在损伤之前作为疾病预防的一种手段。然而，NRF2的长时间表达已被证明通过诱导化疗药物的代谢和外排来保护癌细胞，导致对癌症药物的内在和获得性化疗耐药。这种效应被称为NRF2的“阴暗面”。为了对抗这种化学耐药，我们的团队发现了第一个NRF2抑制剂，天然产物brusatol，然而其抑制机制以前是未知的。在本报告中，我们发现brusatols的作用方式不是通过直接抑制NRF2通路，而是通过抑制帽依赖性和帽非依赖性蛋白翻译，这对包括NRF2在内的许多短寿命蛋白都有影响。因此，仍需要开发新一代毒性有限、脱靶效应有限的特异性NRF2抑制剂，用于NRF2高表达癌症的增敏辅助治疗。
The NRF2 pathway activates a cell survival response when cells are exposed to xenobiotics or are under oxidative stress. Therapeutic activation of NRF2 can also be used prior to insult as a means of disease prevention. However, prolonged expression of NRF2 has been shown to protect cancer cells by inducing the metabolism and efflux of chemotherapeutics, leading to both intrinsic and acquired chemoresistance to cancer drugs. This effect has been termed the “dark side” of NRF2. In an effort to combat this chemoresistance, our group discovered the first NRF2 inhibitor, the natural product brusatol, however the mechanism of inhibition was previously unknown. In this report, we show that brusatols mode of action is not through direct inhibition of the NRF2 pathway, but through the inhibition of both cap-dependent and cap-independent protein translation, which has an impact on many short-lived proteins, including NRF2. Therefore, there is still a need to develop a new generation of specific NRF2 inhibitors with limited toxicity and off-target effects that could be used as adjuvant therapies to sensitize cancers with high expression of NRF2.