Chen Xin-Yi, Chen Xin, Liang Xiao-Hui, Lu Dong, Pan Rong-Rong, Xiong Qing-Yi, Liu Xiao-Xia, Lin Jia-Yi, Zhang Li-Jun, Chen Hong-Zhuan, Jin Jin-Mei, Zhang Wei-Dong, Luan Xin
Shanghai Frontiers Science Center for Chinese Medicine Chemical Biology; Institute of Interdisciplinary Integrative Medicine Research and Shuguang Hospital; Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Institute of Medicinal Plant Development, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, 100700, China.
Acta Pharmacol Sin. 2025 May 15. doi: 10.1038/s41401-025-01562-2.
Head and neck squamous cell carcinoma (HNSCC) cells exhibit a high dependency on glutamine metabolism, making it an attractive target. Despite the well-established link between glutamine reliance and tumor progression, the specific role of glutamine transporters in HNSCC remains poorly understood. The alanine-serine-cysteine transporter 2 (ASCT2), a key glutamine transporter, is overexpressed in HNSCC, and its silencing has been shown to reduce intracellular glutamine and glutathione levels, inhibiting tumor growth. These facts suggest that targeting ASCT2-mediated glutamine uptake could offer a promising therapeutic strategy for HNSCC. But no clinically approved drugs directly target ASCT2, and challenges such as the limited stability of antisense oligonucleotides persist. In this study we evaluated the correlation between ASCT2-mediate glutamine metabolism and its impact on HNSCC patients. We established a virtual screening method followed by cytotoxic assays to identify small molecules that specifically target ASCT2. Among the top 15 candidates, we identified yuanhuacine (YC) as the most potent antitumor compound with IC values of 1.43, 6.62, and 6.46 μM against HN6, CAL33, and SCC7 cells, respectively. We demonstrated that YC (0.3-5 μM) dose-dependently induced ASCT2 degradation by recruiting the E3 ubiquitin ligase RNF5, inhibiting glutamine uptake in HN6 cells. This disruption led to mitochondrial dysfunction and enhanced the therapeutic efficacy of YC. Our results highlight YC as a promising regulator of ASCT2-mediated glutamine metabolism in HNSCC.
头颈部鳞状细胞癌（HNSCC）细胞对谷氨酰胺代谢高度依赖，使其成为一个有吸引力的靶点。尽管谷氨酰胺依赖与肿瘤进展之间的联系已得到充分证实，但谷氨酰胺转运体在HNSCC中的具体作用仍知之甚少。丙氨酸-丝氨酸-半胱氨酸转运体2（ASCT2）是一种关键的谷氨酰胺转运体，在HNSCC中过度表达，其沉默已被证明可降低细胞内谷氨酰胺和谷胱甘肽水平，抑制肿瘤生长。这些事实表明，靶向ASCT2介导的谷氨酰胺摄取可能为HNSCC提供一种有前景的治疗策略。但目前尚无临床批准的直接靶向ASCT2的药物，反义寡核苷酸稳定性有限等挑战依然存在。在本研究中，我们评估了ASCT2介导的谷氨酰胺代谢与其对HNSCC患者影响之间的相关性。我们建立了一种虚拟筛选方法，随后进行细胞毒性试验，以鉴定特异性靶向ASCT2的小分子。在15个最佳候选物中，我们确定芫花酯（YC）是最有效的抗肿瘤化合物，对HN6、CAL33和SCC7细胞的IC值分别为1.43、6.62和6.46μM。我们证明，YC（0.3 - 5μM）通过招募E3泛素连接酶RNF5剂量依赖性地诱导ASCT2降解，抑制HN6细胞中的谷氨酰胺摄取。这种破坏导致线粒体功能障碍，并增强了YC的治疗效果。我们的结果突出了YC作为HNSCC中ASCT2介导的谷氨酰胺代谢的一种有前景的调节剂。
