NPS‐2143 inhibit glioma progression by suppressing autophagy through mediating AKT–mTOR pathway

Abstract

Gliomas are the most common tumours in the central nervous system. In the present study, we aimed to find a promising anti‐glioma compound and investigate the underlying molecular mechanism. Glioma cells were subjected to the 50 candidate compounds at a final concentration of 10 μM for 72 h, and CCK‐8 was used to evaluate their cytotoxicity. NPS‐2143, an antagonist of calcium‐sensing receptor (CASR), was selected for further study due to its potent cytotoxicity to glioma cells. Our results showed that NPS‐2143 could inhibit the proliferation of glioma cells and induce G1 phase cell cycle arrest. Meanwhile, NPS‐2143 could induce glioma cell apoptosis by increasing the caspase‐3/6/9 activity. NPS‐2143 impaired the immigration and invasion ability of glioma cells by regulating the epithelial–mesenchymal transition process. Mechanically, NPS‐2143 could inhibit autophagy by mediating the AKT–mTOR pathway. Bioinformatic analysis showed that the prognosis of glioma patients with low expression of CASR mRNA was better than those with high expression of CASR mRNA. Gene set enrichment analysis showed that CASR was associated with cell adhesion molecules and lysosomes in glioma. The nude mice xenograft model showed NPS‐2143 could suppress glioma growth in vivo. In conclusion, NPS‐2143 can suppress the glioma progression by inhibiting autophagy.

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“…After transfection, the cells received treatment involving the CCK-8 reagent (ab228554, Abcam, USA) at 24, 48, and 72 h and incubated for a specified duration adhering to the manufacturer's prescribed guidance. Subsequently, the absorbance values post-reaction were measured using a spectrophotometer (1681150, Bio‐Rad, USA) at a wavelength of 450nm to quantify the proliferative activity of the cells (Nie et al 2024 ).…”