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.

中文翻译：

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NPS-2143 通过介导 AKT-mTOR 通路抑制自噬来抑制神经胶质瘤进展

神经胶质瘤是中枢神经系统中最常见的肿瘤。在本研究中，我们旨在寻找一种有前途的抗神经胶质瘤化合物并研究其潜在的分子机制。将终浓度为 10 μM 的 50 种候选化合物置于胶质瘤细胞中 72 小时，并使用 CCK-8 评估其细胞毒性。 NPS-2143 是一种钙敏感受体 (CASR) 拮抗剂，因其对神经胶质瘤细胞具有强大的细胞毒性而被选择进行进一步研究。我们的结果表明，NPS-2143 可以抑制胶质瘤细胞的增殖并诱导 G1 期细胞周期停滞。同时，NPS-2143可以通过增加caspase-3/6/9活性来诱导胶质瘤细胞凋亡。 NPS-2143通过调节上皮-间质转化过程损害胶质瘤细胞的迁移和侵袭能力。从机械角度来说，NPS-2143 可以通过介导 AKT-mTOR 通路来抑制自噬。生物信息学分析显示低表达的胶质瘤患者的预后CASRmRNA 优于高表达的CASRmRNA。基因集富集分析表明，CASR 与神经胶质瘤中的细胞粘附分子和溶酶体相关。裸鼠异种移植模型显示 NPS-2143 可以抑制体内神经胶质瘤的生长。总之，NPS-2143可以通过抑制自噬来抑制神经胶质瘤的进展。