Liu Yi, Ma Yanhui, Zhou Bingqian, Bian Bingxian, Zhou Yunlan, Chen Shiyu, Zhang Peng, Shen Lisong, Chen Hui
Department of Clinical Laboratory, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, 1665 Kongjiang Road, Shanghai, 200092, China.
Institute of Artificial Intelligence Medicine, Shanghai Academy of Experimental Medicine, Shanghai, China.
Cell Mol Life Sci. 2025 May 6;82(1):194. doi: 10.1007/s00018-025-05723-8.
Gastric cancer stem cells (GCSCs) play a crucial role in the initiation, progression, recurrence and therapeutic resistance, contributing to a poor prognosis. Consequently, GCSCs are deemed to be a potential therapeutic target for gastric cancer (GC). Although β-catenin is a well-recognized therapeutic target for GC and several inhibitors have demonstrated potent anti-tumor effects, there is a dearth of therapeutic agents targeting β-catenin for clinical therapy. In this study, we carried out high-throughput screening of clinically approved drugs to identify effective inhibitors of β-catenin. The results revealed that the antibiotic drug, clofoctol (CFT) effectively reduced the β-catenin level, attenuated stemness traits both in vitro and in vivo, and induced necroptosis of GCSCs. Further analyzing of downstream genes and targeted proteins, we found that CFT inhibited GCSCs viability by binding to the SUMO E3 ligase RanBP2, thereby suppressing the SerpinE1/β-catenin axis and activating TNF-mediated necroptosis. These results indicate that CFT may exert potent therapeutic effects against GC by targeting β-catenin and inhibiting the viability of GCSCs.
胃癌干细胞（GCSCs）在胃癌的起始、进展、复发及治疗抵抗中发挥着关键作用，导致预后不良。因此，GCSCs被认为是胃癌（GC）潜在的治疗靶点。尽管β-连环蛋白是公认的GC治疗靶点，且几种抑制剂已显示出强大的抗肿瘤作用，但临床上缺乏针对β-连环蛋白的治疗药物。在本研究中，我们对临床批准的药物进行了高通量筛选，以确定β-连环蛋白的有效抑制剂。结果显示，抗生素药物氯甲酚（CFT）能有效降低β-连环蛋白水平，在体外和体内均减弱干性特征，并诱导GCSCs发生坏死性凋亡。通过对下游基因和靶向蛋白的进一步分析，我们发现CFT通过与小泛素样修饰物E3连接酶RanBP2结合来抑制GCSCs的活力，从而抑制丝氨酸蛋白酶抑制剂E1/β-连环蛋白轴并激活肿瘤坏死因子介导的坏死性凋亡。这些结果表明，CFT可能通过靶向β-连环蛋白并抑制GCSCs的活力对GC发挥强大的治疗作用。
