期刊
CELL CHEMICAL BIOLOGY
卷 26, 期 3, 页码 366-+出版社
CELL PRESS
DOI: 10.1016/j.chembiol.2018.11.013
关键词
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资金
- NIH [CA203257, CA175105, T32 DA016176]
- CCSG [P30CA177558]
- National Center for Advancing Translational Sciences [UL1TR000117, UL1TR001998]
- University of Kentucky College of Pharmacy and Markey Cancer Center
- Office of the Vice President for Research
- Markey Cancer Center
- NCI Center Core support grant [P30CA177558]
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.
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