School of Medicine, Shenzhen Campus of Sun Yat-sen University, Sun Yat-sen University, Shenzhen, China.
Department of Infectious Diseases & Department of Hospital Infection Management, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
Life Sci. 2024 Sep 15;353:122918. doi: 10.1016/j.lfs.2024.122918. Epub 2024 Jul 19.
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.
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.
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.
NC inhibits mTORC1 signaling through nutrient sensing and directly targets IGF2R for lysosomal degradation, providing mechanistic insights into the MOA of NC.
盐酸荜茇宁（NC）是一种从两面针（Zanthoxylum nitidum（Roxb.）DC）中提取的天然植物生物碱，具有多种生物活性，包括抗肿瘤、抗炎和其他治疗作用。然而，NC 的主要靶点和作用机制（MOA）尚未明确界定。
我们通过 CRISPR/Cas9 基因编辑技术生成的野生型和基因敲除细胞系中的免疫印迹和荧光显微镜观察，研究了 NC 对 mTORC1 信号的影响。我们通过药物亲和反应靶标稳定性（DARTS）方法确定 IGF2R 是 NC 的直接靶标。我们使用小鼠黑色素瘤 B16 肿瘤异种移植模型研究了 NC 的抗肿瘤作用。
NC 通过激活转录因子 4（ATF4）介导的 sestrin2 诱导，靶向氨基酸感应信号，抑制 mTORC1 活性。NC 直接与 IGF2R 结合，并促进其溶酶体降解。此外，NC 对各种癌细胞表现出强大的细胞毒性，并抑制 B16 肿瘤异种移植。
NC 通过营养感应抑制 mTORC1 信号，直接靶向 IGF2R 进行溶酶体降解，为 NC 的 MOA 提供了机制见解。
