He Yi-Fu, Liu Yi-Ping, Liao Jin-Zhuang, Gan Yu, Li Xiaoying, Wang Rui-Rui, Wang Fang, Zhou Jun, Zhou Li
Department of Obstetrics and Gynecology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.
Department of Oncology, National Clinical Research Center for Geriatric Disorders, Xiangya Hospital, Central South University, Changsha 410008, P. R. China.
Am J Chin Med. 2024;52(3):865-884. doi: 10.1142/S0192415X24500356. Epub 2024 May 25.
Ovarian cancer is a common, highly lethal tumor. Herein, we reported that S-phase kinase-associated protein 2 (Skp2) is essential for the growth and aerobic glycolysis of ovarian cancer cells. Skp2 was upregulated in ovarian cancer tissues and associated with poor clinical outcomes. Using a customized natural product library screening, we found that xanthohumol inhibited aerobic glycolysis and cell viability of ovarian cancer cells. Xanthohumol facilitated the interaction between E3 ligase Cdh1 and Skp2 and promoted the Ub-K48-linked polyubiquitination of Skp2 and degradation. Cdh1 depletion reversed xanthohumol-induced Skp2 downregulation, enhancing HK2 expression and glycolysis in ovarian cancer cells. Finally, a xenograft tumor model was employed to examine the antitumor efficacy of xanthohumol . Collectively, we discovered that xanthohumol promotes the binding between Skp2 and Cdh1 to suppress the Skp2/AKT/HK2 signal pathway and exhibits potential antitumor activity for ovarian cancer cells.
卵巢癌是一种常见的、致死率很高的肿瘤。在此，我们报告称，S期激酶相关蛋白2（Skp2）对卵巢癌细胞的生长和有氧糖酵解至关重要。Skp2在卵巢癌组织中上调，并与不良临床结果相关。通过定制的天然产物文库筛选，我们发现黄腐酚抑制卵巢癌细胞的有氧糖酵解和细胞活力。黄腐酚促进E3连接酶Cdh1与Skp2之间的相互作用，并促进Skp2的泛素K48连接的多聚泛素化和降解。Cdh1的缺失逆转了黄腐酚诱导的Skp2下调，增强了卵巢癌细胞中HK2的表达和糖酵解。最后，采用异种移植肿瘤模型来检测黄腐酚的抗肿瘤疗效。总体而言，我们发现黄腐酚促进Skp2与Cdh1之间的结合，以抑制Skp2/AKT/HK2信号通路，并对卵巢癌细胞表现出潜在的抗肿瘤活性。
