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

  • Cell Chem Biol. 2019 Mar 21;26(3):366-377.e12. doi: 10.1016/j.chembiol.2018.11.013.
Qing Ye  1 ,  Yinan Zhang  2 ,  Yanan Cao  1 ,  Xiachang Wang  2 ,  Yubin Guo  1 ,  Jing Chen  3 ,  Jamie Horn  4 ,  Larissa V Ponomareva  4 ,  Luksana Chaiswing  5 ,  Khaled A Shaaban  4 ,  Qiou Wei  5 ,  Bradley D Anderson  6 ,  Daret K St Clair  5 ,  Haining Zhu  3 ,  Markos Leggas  6 ,  Jon S Thorson  7 ,  Qing-Bai She  8
Affiliations
  • 1. Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA.
  • 2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA; Jiangsu Key Laboratory for Functional Substances of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu 210047, China.
  • 3. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Molecular and Cellular Biochemistry, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
  • 4. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.
  • 5. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Toxicology and Cancer Biology, College of Medicine, University of Kentucky, Lexington, KY 40536, USA.
  • 6. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA.
  • 7. Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, Lexington, KY 40536, USA; Center for Pharmaceutical Research and Innovation, University of Kentucky, Lexington, KY 40536, USA. Electronic address: [email protected].
  • 8. Department of Pharmacology and Nutritional Sciences, College of Medicine, University of Kentucky, Lexington, KY 40536, USA; Markey Cancer Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address: [email protected].
PMID: 30661989 DOI: 10.1016/j.chembiol.2018.11.013
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.

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