AXL tyrosine kinase inhibitor TP-0903 induces ROS trigger neuroblastoma cell apoptosis via targeting the miR-335-3p/DKK1 expression

  • Cell Death Discov. 2025 Aug 13;11(1):378. doi: 10.1038/s41420-025-02681-9.
Tsai-Yi Tseng  #  1  2 ,  Shao-Hsuan Kao  #  2  3 ,  Shun-Fa Yang  2  3 ,  Yi-Chen Lin  2 ,  Chu-Liang Lin  2 ,  Juei-Liang Chen  4 ,  Chien-Min Chen  5  6  7 ,  Yi-Hsien Hsieh  8  9
Affiliations
  • 1. Division of Pediatric Surgery, Department of Surgery, Children's Hospital of China Medical University, Taichung, Taiwan.
  • 2. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan.
  • 3. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan.
  • 4. Department of Pathology & Laboratory Medicine, Taichung Veterans General Hospital, Taichung, Taiwan.
  • 5. Division of Neurosurgery, Department of Surgery, Changhua Christian Hospital, Changhua, Taiwan. [email protected].
  • 6. Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan. [email protected].
  • 7. Department of Biomedical Sciences National Chung Cheng University, Chiayi, Taiwan. [email protected].
  • 8. Institute of Medicine, Chung Shan Medical University, Taichung, Taiwan. [email protected].
  • 9. Department of Medical Research, Chung Shan Medical University Hospital, Taichung, Taiwan. [email protected].
  • # Contributed equally.
PMID: 40804038 DOI: 10.1038/s41420-025-02681-9
Abstract

Neuroblastoma (NB) is an aggressive Cancer and has poor prognosis in children. TP-0903, a multi-kinase inhibitor, shows inhibitory effects on NB but the mechanistic act is not completely explored. Here, we aimed to explore the Anticancer activity of TP-0903 against NB cells and its underlying mechanism. In this study, our findings showed that TP-0903 ( ≥ 50 nM) significantly inhibited the growth of SH-SY5Y and Neuro-2a cells. Further results revealed that TP-0903 remarkably triggered cell Apoptosis, mitochondrial membrane potential (MMP) lose, and Caspase activation. Microarray assay, qRT-PCR, and Western blotting results indicated that DKK1 was downregulated by TP-0903. Notably, DKK1 is upregulated in NB tissues as comparing to normal tissues. Moreover, silencing DKK1 promoted TP-0903-induced Apoptosis and Caspase activation, and predicted the binding of TP-0903 to DKK1. In addition, we found that 3'-UTR of DKK1 had a potential target region for miR-335-3p and TP-0903 upregulated miR-335-3p expression. Of important, miR-335-3p mimic combined with TP-0903 provoked higher Apoptosis and Caspase activation than TP-0903 alone. We also observed that TP-0903 increased cellular Reactive Oxygen Species (ROS), and inhibition of ROS reduced the Apoptosis, PARP cleavage, and miR-335-3p, while increasing DKK1 in response to TP-0903. Finally, we demonstrated that TP-0903 significantly diminished the tumor growth and DKK1 expression in xenograft mice. Collectively, our findings indicate that TP-0903 triggers apoptotic cell death of NB cells, attributing to the ROS-mediated miR-335-3p upregulation and the consequent DKK1 downregulation.

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