Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects

Qing Ye, Yinan Zhang, Yanan Cao, Xiachang Wang, Yubin Guo, Jing Chen, Jamie Horn, Larissa V. Ponomareva, Luksana Chaiswing, Khaled A. Shaaban, Qiou Wei, Bradley D. Anderson, Daret K. St Clair, Haining Zhu, Markos Leggas, Jon S. Thorson, Qing Bai She

Research output: Contribution to journalArticlepeer-review

16 Scopus citations

Abstract

Peroxiredoxin 1 (Prx1) and glutaredoxin 3 (Grx3) are two major antioxidant proteins that play a critical role in maintaining redox homeostasis for tumor progression. Here, we identify the prototypical pyranonaphthoquinone natural product frenolicin B (FB) as a selective inhibitor of Prx1 and Grx3 through covalent modification of active-site cysteines. FB-targeted inhibition of Prx1 and Grx3 results in a decrease in cellular glutathione levels, an increase of reactive oxygen species (ROS), and concomitant inhibition of cancer cell growth, largely by activating the peroxisome-bound tuberous sclerosis complex to inhibit mTORC1/4E-BP1 signaling axis. FB structure-activity relationship studies reveal a positive correlation between inhibition of 4E-BP1 phosphorylation, ROS-mediated cancer cell cytotoxicity, and suppression of tumor growth in vivo. These findings establish FB as the most potent Prx1/Grx3 inhibitor reported to date and also notably highlight 4E-BP1 phosphorylation status as a potential predictive marker in response to ROS-based therapies in cancer. Ye, Zhang et al. identify frenolicin B as a potent and selective inhibitor of Prx1 and Grx3, leading to generation of ROS and subsequent repression of mTORC1/4E-BP1-mediated translational control of tumor growth with the potential to be developed into a new class of anticancer agents.

Original languageEnglish (US)
Pages (from-to)366-377.e12
JournalCell Chemical Biology
Volume26
Issue number3
DOIs
StatePublished - Mar 21 2019
Externally publishedYes

Keywords

  • 4E-BP1
  • AKT
  • eIF4E
  • frenolicin B
  • glutaredoxin 3
  • mTORC1
  • peroxiredoxin 1
  • pyranonaphthoquinone
  • RAS
  • ROS

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmacology
  • Drug Discovery
  • Clinical Biochemistry

Fingerprint

Dive into the research topics of 'Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects'. Together they form a unique fingerprint.

Cite this