1. Frenolicin B Targets Peroxiredoxin 1 and Glutaredoxin 3 to Trigger ROS/4E-BP1-Mediated Antitumor Effects.
- Author
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Ye Q, Zhang Y, Cao Y, Wang X, Guo Y, Chen J, Horn J, Ponomareva LV, Chaiswing L, Shaaban KA, Wei Q, Anderson BD, St Clair DK, Zhu H, Leggas M, Thorson JS, and She QB
- Subjects
- Adaptor Proteins, Signal Transducing antagonists & inhibitors, Adaptor Proteins, Signal Transducing genetics, Animals, Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Cell Cycle Proteins antagonists & inhibitors, Cell Cycle Proteins genetics, Cell Line, Tumor, Cell Survival drug effects, Glutaredoxins antagonists & inhibitors, Humans, Male, Mechanistic Target of Rapamycin Complex 1 metabolism, Mice, Mice, Nude, Naphthoquinones chemistry, Naphthoquinones pharmacology, Naphthoquinones therapeutic use, Neoplasms drug therapy, Neoplasms pathology, Peroxiredoxins antagonists & inhibitors, Phosphorylation drug effects, RNA Interference, RNA, Small Interfering metabolism, Signal Transduction drug effects, Transplantation, Heterologous, Adaptor Proteins, Signal Transducing metabolism, Antineoplastic Agents chemistry, Cell Cycle Proteins metabolism, Glutaredoxins metabolism, Peroxiredoxins metabolism, Reactive Oxygen Species metabolism
- 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., (Published by Elsevier Ltd.)
- Published
- 2019
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