Objective To investigate the effects and related molecular mechanisms of esketamine on the proliferation, epithelial-mesenchymal transition (EMT), and stem cell properties of colorectal cancer (CRC) cells.

Methods CRC cell line SW480 was cultured with varying concentrations of esketamine, and the cells were divided into blank group (0 μmol/L), low-concentration group (1 μmol/L), medium-concentration group (5 μmol/L) and high-concentration group (10 μmol/L). Cell proliferation activity was assessed using the EdU proliferation assay, cell spheroid-forming ability was evaluated via the spheroid formation assay, cell migration capacity was measured using the scratch assay, cell invasion ability was determined through the transwell assay, and the expression levels of tumor stem cell property markersNANOG homeobox (NANOG), SRY-box transcription factor (SOX) 2, SOX4, the neurogenic locus Notch homolog protein 1 (Notch1) receptor and the Notch1 intracellular domain (Notch1 ICD) were detected by western blot. A recovery test was conducted by adding the Notch1 receptor agonist Jagged1 to the culture groups with different concentrations of esketamine.

Results Compared with the blank group, esketamine significantly inhibited the proliferation activity, spheroid-forming ability, migration ability, and invasion ability of CRC cells in a concentration-dependent manner. The intracellular expression levels of SOX2, SOX4, NANOG, and Notch1 ICD proteins were significantly decreased, while the expression level of the Notch1 receptor was significantly increased in the esketamine groups (P < 0.05). After the addition of Jagged1, the inhibitory effects of esketamine on the proliferation activity, metastatic ability, and stem cell properties of CRC cells were alleviated.

Conclusion Esketamine inhibits CRC cell proliferation, metastasis, EMT, and stem cell properties by reducing the activation level of the Notch1 receptor, demonstrating a potential for clinical anti-tumor applications.