1. Nitidine chloride inhibits mTORC1 signaling through ATF4-mediated Sestrin2 induction and targets IGF2R for lysosomal degradation.
- Author
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Chen F, Peng S, Li C, Yang F, Yi Y, Chen X, Xu H, Cheng B, Xu Y, and Xie X
- Subjects
- Animals, Mice, Humans, Mice, Inbred C57BL, Cell Line, Tumor, Melanoma, Experimental drug therapy, Melanoma, Experimental metabolism, Melanoma, Experimental pathology, Nuclear Proteins metabolism, Nuclear Proteins genetics, Xenograft Model Antitumor Assays, Sestrins, Mechanistic Target of Rapamycin Complex 1 metabolism, Activating Transcription Factor 4 metabolism, Activating Transcription Factor 4 genetics, Signal Transduction drug effects, Lysosomes metabolism, Lysosomes drug effects, Benzophenanthridines pharmacology
- Abstract
Aims: Nitidine chloride (NC), a natural phytochemical alkaloid derived from Zanthoxylum nitidum (Roxb.) DC, exhibits multiple bioactivities, including antitumor, anti-inflammatory, and other therapeutic effects. However, the primary targets of NC and the mechanism of action (MOA) have not been explicitly defined., Methods: We explored the effects of NC on mTORC1 signaling by immunoblotting and fluorescence microscopy in wild-type and gene knockout cell lines generated by the CRISPR/Cas9 gene editing technique. We identified IGF2R as a direct target of NC via the drug affinity-responsive target stability (DARTS) method. We investigated the antitumor effects of NC using a mouse melanoma B16 tumor xenograft model., Key Findings: NC inhibits mTORC1 activity by targeting amino acid-sensing signaling through activating transcription factor 4 (ATF4)-mediated Sestrin2 induction. NC directly binds to IGF2R and promotes its lysosomal degradation. Moreover, NC displayed potent cytotoxicity against various cancer cells and inhibited B16 tumor xenografts., Significance: NC inhibits mTORC1 signaling through nutrient sensing and directly targets IGF2R for lysosomal degradation, providing mechanistic insights into the MOA of NC., Competing Interests: Declaration of competing interest The authors declare no competing interests., (Copyright © 2024 Elsevier Inc. All rights reserved.)
- Published
- 2024
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