Guo Hui, Li Wanhu, Pan Guoyou, Wang Cong, Li Dapeng, Liu Naifu, Sheng Xiugui, Yuan Lingqin
Department of Gynecologic Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Department of Medical Imaging, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong, China.
Anticancer Agents Med Chem. 2023;23(2):210-221. doi: 10.2174/1871520622666220513163341.
Glutamine is one of the primary nutrients utilized by cancer cells for energy production and biosynthesis. Hence, interfering with glutamine metabolism may impose anti-tumor effects.
In this study, we assessed the anti-tumorigenic effects of glutaminase-1 enzyme (GLS1) inhibition in endometrial cancer in vitro and in vivo.
The human endometrial cancer cell lines Ishikawa and HEC-1B were used. The effects of compound 968 on cell proliferation, cell cycle, apoptosis, cellular stress, and AKT/mTOR pathway inhibition were assessed. The synergistic effects of compound 968 and paclitaxel were also analyzed. The in vivo effect of compound 968 was evaluated using tumor xenografts.
We found that the GLS1-targeting compound 968 was able to reduce cancer cell proliferation in a dose- and time-dependent manner. Compound 968 combined with a low concentration of paclitaxel showed stronger inhibitory effects. Further analyses indicated that compound 968 induced cell cycle arrest at the G1 phase, as well as increased the production of cellular reactive oxygen species (ROS) and promoted cellular stress and cancer cell apoptosis. Additionally, the treatment of endometrial cancer with compound 968 downregulated the expression of GLS1 and cyclin D1 and upregulated the expression of P21 and E-cadherin. Moreover, the treatment of endometrial cancer cells with compound 968 significantly reduced the levels of phospho-S6 ribosomal protein and phospho-AKT (Ser473), indicative of AKT/mTOR/S6 signaling pathway inhibition. In xenograft mouse models of endometrial cancer, compound 968 significantly suppressed tumor growth. In addition, western blotting analysis indicated that GLS1 expression was upregulated in human endometrial cancer tissues.
Compound 968 may be a promising approach for the management of human endometrial cancer.
谷氨酰胺是癌细胞用于能量产生和生物合成的主要营养物质之一。因此，干扰谷氨酰胺代谢可能具有抗肿瘤作用。
在本研究中，我们评估了谷氨酰胺酶-1（GLS1）抑制在体外和体内对子宫内膜癌的抗肿瘤作用。
使用人子宫内膜癌细胞系 Ishikawa 和 HEC-1B。评估化合物 968 对细胞增殖、细胞周期、凋亡、细胞应激以及 AKT/mTOR 通路抑制的影响。还分析了化合物 968 与紫杉醇的协同作用。使用肿瘤异种移植模型评估化合物 968 的体内作用。
我们发现靶向 GLS1 的化合物 968 能够以剂量和时间依赖性方式降低癌细胞增殖。化合物 968 与低浓度紫杉醇联合显示出更强的抑制作用。进一步分析表明，化合物 968 诱导细胞周期停滞在 G1 期，增加细胞活性氧（ROS）的产生，促进细胞应激和癌细胞凋亡。此外，用化合物 968 治疗子宫内膜癌下调了 GLS1 和细胞周期蛋白 D1 的表达，上调了 P21 和 E-钙黏蛋白的表达。而且，用化合物 968 处理子宫内膜癌细胞显著降低了磷酸化 S6 核糖体蛋白和磷酸化 AKT（Ser473）的水平，表明 AKT/mTOR/S6 信号通路受到抑制。在子宫内膜癌异种移植小鼠模型中，化合物 968 显著抑制肿瘤生长。此外，蛋白质印迹分析表明 GLS1 在人子宫内膜癌组织中表达上调。
化合物 968 可能是治疗人类子宫内膜癌的一种有前景的方法。
