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.
Published by Elsevier Ltd.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Adaptor Proteins, Signal Transducing / antagonists & inhibitors
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Adaptor Proteins, Signal Transducing / genetics
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Adaptor Proteins, Signal Transducing / metabolism*
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Animals
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Antineoplastic Agents / chemistry*
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Antineoplastic Agents / pharmacology
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Antineoplastic Agents / therapeutic use
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Cell Cycle Proteins / antagonists & inhibitors
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Cell Cycle Proteins / genetics
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Cell Cycle Proteins / metabolism*
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Cell Line, Tumor
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Cell Survival / drug effects
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Glutaredoxins / antagonists & inhibitors
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Glutaredoxins / metabolism*
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Humans
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Male
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Mechanistic Target of Rapamycin Complex 1 / metabolism
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Mice
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Mice, Nude
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Naphthoquinones / chemistry
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Naphthoquinones / pharmacology
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Naphthoquinones / therapeutic use
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Neoplasms / drug therapy
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Neoplasms / pathology
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Peroxiredoxins / antagonists & inhibitors
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Peroxiredoxins / metabolism*
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Phosphorylation / drug effects
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RNA Interference
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RNA, Small Interfering / metabolism
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Reactive Oxygen Species / metabolism*
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Signal Transduction / drug effects
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Transplantation, Heterologous
Substances
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Adaptor Proteins, Signal Transducing
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Antineoplastic Agents
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Cell Cycle Proteins
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EIF4EBP1 protein, human
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Glutaredoxins
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Naphthoquinones
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RNA, Small Interfering
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Reactive Oxygen Species
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frenolicin B
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Peroxiredoxins
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Mechanistic Target of Rapamycin Complex 1