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.
Bibliographical noteFunding Information:
The authors are grateful to Dr. Jerry Pelletier for kindly providing the dual Firefly/Renilla reporter constructs and to Dr. Matthew Dodson and Montserrat Rojo de la Vega for their critical review of this manuscript. This work was funded by the National Cancer Institute (RO1CA154377).
© 2017 Wiley Periodicals, Inc.
- protein translation
ASJC Scopus subject areas
- Molecular Biology
- Cancer Research