2. Academic Validation
  3. The hidden potential of solasonine: Targeting non-small cell lung cancer (NSCLC) metastasis through GATM and Smad2 pathways

The hidden potential of solasonine: Targeting non-small cell lung cancer (NSCLC) metastasis through GATM and Smad2 pathways

  • Phytomedicine. 2025 Feb 2:139:156455. doi: 10.1016/j.phymed.2025.156455.
Cheng Hu 1,  Jia-Qi Zhang 2,  Xiao-Yu Zhuang 1,  Zhen-Duo Zhao 2,  Xiao-Jing Qian 2,  Ying Chen 3
Affiliations

Affiliations

  • 1 Science and Technology Experiment Center, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
  • 2 Department of Pharmacy, Shanghai Municipal Hospital of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai 200071, China.
  • 3 Nanxiang Branch of Ruijin Hospital, Shanghai 201802, China. Electronic address: lcys7382@163.com.
PMID: 39922150 DOI: 10.1016/j.phymed.2025.156455
Abstract

Purpose: To study the pharmacological effects of solasonine (Sol) in inhibiting non-small cell lung Cancer (NSCLC) metastasis.

Methods: The pharmacological effects of solasonine were examined in vitro by continuous induction of NSCLC cells by no treatment, or TGF-β, or creatine. Cell migration and invasion were assessed via wound healing and transwell assays, and the levels of epithelial-mesenchymal transition (EMT) markers were determined using immunofluorescence and Western Blot. Solasonine's ability to bind to TGF-β and creatine transferases and isoenzymes was assessed by TCGA, KMPLOT database, cellular thermal shift assay (CETSA), and molecular docking assay. In vivo, two types of NSCLC cells were injected into mice using the tail vein. Solasonine's effect on tumor metastasis was determined using in vivo fluorescent probes, hematoxylin-eosin staining assay, and immunofluorescence.

Results: Unlike traditional therapies targeting TGF-β receptors, Sol was shown to inhibit NSCLC metastasis through a novel mechanism independent of TGF-β signaling. Creatine was found to promote NSCLC metastasis in vitro by enhancing cell migration, invasion, and EMT-related protein expression, and in vivo by increasing metastasis to the liver. These effects were mediated by the activation of SMAD2 phosphorylation and EMT independently of TGF-β. Sol effectively counteracted these effects by targeting guanidinoacetate methyltransferase (GATM) with high binding affinity, thereby suppressing the TTK-mediated SMAD2 pathway and significantly reducing metastasis to the lungs and liver, as confirmed by HE staining and fluorescence imaging.

Conclusions: This study identifies solasonine as a novel inhibitor of NSCLC metastasis, acting through the GATM and SMAD2 pathways to counter creatine-induced metastasis. These findings underscore the potential of Sol as a therapeutic candidate for metastatic NSCLC.

Keywords

EMT; GATM; NSCLC metastasis; Smad; Solasonine.

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