title: Brusatol overcomes chemoresistance through inhibition of protein translation.
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.
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Bryan
authors.initials: B
authors.lastname: Harder
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Wang
authors.initials: W
authors.lastname: Tian
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: James J
authors.initials: JJ
authors.lastname: La Clair
authors.affiliation: Division of Medical Oncology. School of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado.
authors.forename: Aik-Choon
authors.initials: AC
authors.lastname: Tan
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Aikseng
authors.initials: A
authors.lastname: Ooi
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.
authors.forename: Eli
authors.initials: E
authors.lastname: Chapman
authors.affiliation: Department of Pharmacology and Toxicology, University of Arizona, Tucson, Arizona.|University of Arizona Cancer Center (UACC), University of Arizona, Tucson, Arizona.
authors.forename: Donna D
authors.initials: DD
authors.lastname: Zhang
mesh_terms: D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects* / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D051267:NF-E2-Related Factor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000187:drug effects*; D036702:Quassins / Q000493:pharmacokinetics / Q000494:pharmacology*; D017423:Sequence Analysis, RNA
chemical_list: D051267:NF-E2-Related Factor 2; C495635:NFE2L2 protein, human; D036702:Quassins; C020237:brusatol
keywords: NRF2; brusatol; cancer; chemoresistance; protein translation