Brusatol overcomes chemoresistance through inhibition of protein translation
Bryan Harder1, Wang Tian1, James J La Clair1
1Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
Abstract:
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 brusatol's 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.
Insights
The natural product brusatol inhibits protein translation, not directly NRF2, impacting cancer cell survival and drug resistance. New NRF2 inhibitors are needed for effective cancer therapy.
Area of Science:
- Molecular Biology
- Cancer Research
- Pharmacology
Background:
- The NRF2 pathway promotes cell survival against stress and xenobiotics.
- Overexpressed NRF2 contributes to chemoresistance by enhancing drug metabolism and efflux.
- This NRF2-mediated chemoresistance is known as the "dark side" of NRF2.
Purpose of the Study:
- To elucidate the mechanism of action of brusatol, the first discovered NRF2 inhibitor.
- To investigate brusatol's effect on the NRF2 pathway and protein translation.
- To identify new therapeutic strategies against NRF2-driven chemoresistance.
Main Methods:
- Investigated brusatol's impact on protein translation.
- Assessed brusatol's effect on NRF2 levels and activity.
- Analyzed brusatol's influence on cap-dependent and cap-independent translation.
Main Results:
- Brusatol inhibits both cap-dependent and cap-independent protein translation.
- Brusatol's mode of action is not direct NRF2 inhibition but rather impacts short-lived proteins, including NRF2.
- This broad translational inhibition affects NRF2 levels and downstream survival responses.
Conclusions:
- Brusatol's mechanism involves general protein translation inhibition, not direct NRF2 targeting.
- There is a critical need for developing specific NRF2 inhibitors with reduced toxicity.
- Targeting NRF2 with novel inhibitors could sensitize resistant cancers to chemotherapy.
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