Brusatol overcomes chemoresistance through inhibition of protein translation

Bryan Harder, Wang Tian, James J. La Clair, Aik-Choon Tan, Aikseng Ooi, Eli Chapman, Donna D. Zhang

Research output: Contribution to journalArticle

27 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1493-1500
Number of pages8
JournalMolecular Carcinogenesis
Volume56
Issue number5
DOIs
Publication statusPublished - 2017 May 1
Externally publishedYes

Fingerprint

Protein Biosynthesis
Neoplasms
Xenobiotics
Biological Products
Cell Survival
Oxidative Stress
Therapeutics
Pharmaceutical Preparations
brusatol
Proteins

Keywords

  • brusatol
  • cancer
  • chemoresistance
  • NRF2
  • protein translation

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research

Cite this

Harder, B., Tian, W., La Clair, J. J., Tan, A-C., Ooi, A., Chapman, E., & Zhang, D. D. (2017). Brusatol overcomes chemoresistance through inhibition of protein translation. Molecular Carcinogenesis, 56(5), 1493-1500. https://doi.org/10.1002/mc.22609

Brusatol overcomes chemoresistance through inhibition of protein translation. / Harder, Bryan; Tian, Wang; La Clair, James J.; Tan, Aik-Choon; Ooi, Aikseng; Chapman, Eli; Zhang, Donna D.

In: Molecular Carcinogenesis, Vol. 56, No. 5, 01.05.2017, p. 1493-1500.

Research output: Contribution to journalArticle

Harder, B, Tian, W, La Clair, JJ, Tan, A-C, Ooi, A, Chapman, E & Zhang, DD 2017, 'Brusatol overcomes chemoresistance through inhibition of protein translation', Molecular Carcinogenesis, vol. 56, no. 5, pp. 1493-1500. https://doi.org/10.1002/mc.22609
Harder B, Tian W, La Clair JJ, Tan A-C, Ooi A, Chapman E et al. Brusatol overcomes chemoresistance through inhibition of protein translation. Molecular Carcinogenesis. 2017 May 1;56(5):1493-1500. https://doi.org/10.1002/mc.22609
Harder, Bryan ; Tian, Wang ; La Clair, James J. ; Tan, Aik-Choon ; Ooi, Aikseng ; Chapman, Eli ; Zhang, Donna D. / Brusatol overcomes chemoresistance through inhibition of protein translation. In: Molecular Carcinogenesis. 2017 ; Vol. 56, No. 5. pp. 1493-1500.
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