SHAO-HSUAN KAOSHUN-FA YANGYI-HSIEN HSIEH2026-10-162026-10-162025-12-01Pure ID: 15188399Pure UUID: 48f3177f-f198-4c93-8920-fa71d99d378310.1038/s41420-025-02681-9https://www.scopus.com/pages/publications/105013303467https://scholars.csmu.edu.tw/handle/123456789/23204Neuroblastoma (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. (Figure presented.)enjournal article