Xanthohumol Promotes Skp2 Ubiquitination Leading to the Inhibition of Glycolysis and Tumorigenesis in Ovarian Cancer.

The American journal of Chinese medicine Pub Date : 2024-01-01 Epub Date: 2024-05-25 DOI:10.1142/S0192415X24500356
Yi-Fu He, Yi-Ping Liu, Jin-Zhuang Liao, Yu Gan, Xiaoying Li, Rui-Rui Wang, Fang Wang, Jun Zhou, Li Zhou
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Abstract

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 in vivo. 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.

黄腐醇促进 Skp2 泛素化,导致抑制糖酵解和卵巢癌的肿瘤发生
卵巢癌是一种常见的高致死性肿瘤。在此,我们报告了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,并与不良临床预后相关。通过定制的天然产物库筛选,我们发现黄腐醇能抑制卵巢癌细胞的有氧糖酵解和细胞活力。黄腐醇能促进E3连接酶Cdh1和Skp2之间的相互作用,并促进Ub-K48连接的Skp2多泛素化和降解。Cdh1的缺失逆转了黄腐醇诱导的Skp2下调,增强了卵巢癌细胞中HK2的表达和糖酵解。最后,我们利用异种移植肿瘤模型研究了黄腐醇在体内的抗肿瘤效果。综上所述,我们发现黄腐醇能促进Skp2与Cdh1的结合,从而抑制Skp2/AKT/HK2信号通路,对卵巢癌细胞具有潜在的抗肿瘤活性。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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