Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects. Issue 3 (21st March 2019)

• Record Type: Journal Article
• Authors: Ye, Qing; Zhang, Yinan; Cao, Yanan; Wang, Xiachang; Guo, Yubin; Chen, Jing; Horn, Jamie; Ponomareva, Larissa V.; Chaiswing, Luksana; Shaaban, Khaled A.; Wei, Qiou; Anderson, Bradley D.; St Clair, Daret K.; Zhu, Haining; Leggas, Markos; Thorson, Jon S.; She, Qing-Bai
• Is Part Of: Cell chemical biology. Volume 26:Issue 3(2019)
• Page Start: 366
• Page End: 377.e12
• Publication Date: 2019-03-21
• Subjects: frenolicin B -- peroxiredoxin 1 -- glutaredoxin 3 -- ROS -- mTORC1 -- 4E-BP1 -- pyranonaphthoquinone -- AKT -- RAS -- eIF4E; Biochemistry -- Periodicals; 572.05
• DOI: 10.1016/j.chembiol.2018.11.013
• Languages: English
• ISSNs: 2451-9456

Abstract

Summary: 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. Graphical Abstract: Highlights: Frenolicin B directly targets Prx1 and Grx3 to induce ROS Frenolicin B-derived ROS inhibits 4E-BP1 phosphorylation and cancer cell growth 4E-BP1 phosphorylation status potentially predicts the cytotoxic level of ROS Optimized inhibitor effectively suppresses tumor growth in vivo Abstract : 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.