一种新型ASCT2抑制剂C118P可阻断谷氨酰胺转运并在乳腺癌中展现出抗肿瘤疗效。
A Novel ASCT2 Inhibitor, C118P, Blocks Glutamine Transport and Exhibits Antitumour Efficacy in Breast Cancer.
作者信息
Lyu Xiao-Dan, Liu Yang, Wang Jia, Wei Yuan-Cheng, Han Yi, Li Xue, Zhang Qian, Liu Zheng-Rui, Li Zheng-Zheng, Jiang Jing-Wei, Hu Hao-Lin, Yuan Sheng-Tao, Sun Li
机构信息
Jiangsu Key Laboratory of Drug Screening, China Pharmaceutical University, Nanjing 210009, China.
School of Medicine and Holistic Integrative Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China.
出版信息
Cancers (Basel). 2023 Oct 20;15(20):5082. doi: 10.3390/cancers15205082.
BACKGROUND
The microtubule protein inhibitor C118P shows excellent anti-breast cancer effects. However, the potential targets and mechanisms of C118P in breast cancer remain unknown.
METHODS
Real-time cellular analysis (RTCA) was used to detect cell viability. Apoptosis and the cell cycle were detected by flow cytometry. Computer docking simulations, surface plasmon resonance (SPR) technology, and microscale thermophoresis (MST) were conducted to study the interaction between C118P and alanine-serine-cysteine transporter 2 (ASCT2). Seahorse XF technology was used to measure the basal oxygen consumption rate (OCR). The effect of C118P in the adipose microenvironment was explored using a co-culture model of adipocytes and breast cancer cells and mouse cytokine chip.
RESULTS
C118P inhibited proliferation, potentiated apoptosis, and induced G2/M cell cycle arrest in breast cancer cells. Notably, ASCT2 was validated as a C118P target through reverse docking, SPR, and MST. C118P suppressed glutamine metabolism and mediated autophagy via ASCT2. Similar results were obtained in the adipocyte-breast cancer microenvironment. Adipose-derived interleukin-6 (IL-6) promoted the proliferation of breast cancer cells by enhancing glutamine metabolism via ASCT2. C118P inhibited the upregulation of ASCT2 by inhibiting the effect of IL-6 in co-cultures.
CONCLUSION
C118P exerts an antitumour effect against breast cancer via the glutamine transporter ASCT2.
背景
微管蛋白抑制剂C118P显示出优异的抗乳腺癌效果。然而，C118P在乳腺癌中的潜在靶点和机制仍不清楚。
方法
采用实时细胞分析（RTCA）检测细胞活力。通过流式细胞术检测细胞凋亡和细胞周期。进行计算机对接模拟、表面等离子体共振（SPR）技术和微量热泳动（MST）以研究C118P与丙氨酸-丝氨酸-半胱氨酸转运蛋白2（ASCT2）之间的相互作用。使用海马XF技术测量基础氧消耗率（OCR）。利用脂肪细胞与乳腺癌细胞的共培养模型和小鼠细胞因子芯片探索C118P在脂肪微环境中的作用。
结果
C118P抑制乳腺癌细胞增殖，增强细胞凋亡，并诱导G2/M期细胞周期阻滞。值得注意的是，通过反向对接、SPR和MST验证ASCT2为C118P的靶点。C118P通过ASCT2抑制谷氨酰胺代谢并介导自噬。在脂肪-乳腺癌微环境中也获得了类似结果。脂肪源性白细胞介素-6（IL-6）通过ASCT2增强谷氨酰胺代谢促进乳腺癌细胞增殖。C118P通过抑制共培养中IL-6的作用抑制ASCT2的上调。
结论
C118P通过谷氨酰胺转运蛋白ASCT2对乳腺癌发挥抗肿瘤作用。
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