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Nitidine chloride inhibits mTORC1 signaling through ATF4-mediated Sestrin2 induction and targets IGF2R for lysosomal degradation.

Published:19 July 2024 DOI: 10.1016/j.lfs.2024.122918 PMID: 39034027
Fengzhi Chen , Shujun Peng , Canrong Li , Fan Yang , Yuguo Yi , Xinyu Chen , Haolun Xu , Baicheng Cheng , Yumin Xu , Xiaoduo Xie

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.

Substances (8)

Materials
Procduct Name CAS Molecular Formula Supplier Price
AZD-8055 1009298-09-2 C25H31N5O4 234 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 234 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 234 suppliers $12.00-$2770.00
AZD-8055 1009298-09-2 C25H31N5O4 234 suppliers $12.00-$2770.00
NITIDINE 6872-57-7 C21H18NO4 27 suppliers Inquiry
NITIDINE 6872-57-7 C21H18NO4 27 suppliers Inquiry
NITIDINE 6872-57-7 C21H18NO4 27 suppliers Inquiry
NITIDINE 6872-57-7 C21H18NO4 27 suppliers Inquiry

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