文章：

橄榄苦苷通过调控泛素化介导的Mcl-1降解发挥抗肿瘤活性

Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity 

原文发布日期：2025-06-12 

英文摘要：

Oral squamous cell carcinoma (OSCC) represents the most common type of malignant oral tumor, with a high prevalence globally. Despite continual advancements in OSCC treatment, the 5-year survival rate remains around 50%, highlighting an urgent need for the development of new and effective therapeutic strategies. Here, we focused on myeloid leukemia 1 (Mcl-1), a well-known oncogenic driver in various human cancers, and systematically explored the therapeutic potential of oleuropein (Ole) through in vitro and in vivo analyses. Our findings demonstrated that Ole suppressed OSCC cell viability dose-dependently. Mechanistically, Ole facilitated β-TRCP-mediated ubiquitination of Mcl-1 by inhibiting the Akt-GSK3β-Mcl-1 pathway and enhancing the collaboration between β-TRCP and Mcl-1, ultimately leading to Mcl-1 degradation. Furthermore, the knockdown of β-TRCP mitigated the inhibitory effects of Ole on OSCC cells. In agreement with our cell-based experiments, animal studies showed that Ole treatment significantly delayed tumor growth without causing toxicity to vital organs. Additionally, whether used alone or combined with radiation, Ole effectively overcame radioresistance in OSCC cells. Our results suggest that Ole is a promising anti-tumor agent capable of treating OSCC by targeting Mcl-1. 

摘要翻译：

口腔鳞状细胞癌（OSCC）是最常见的恶性口腔肿瘤类型，在全球范围内具有高发病率。尽管OSCC的治疗手段不断进步，其五年生存率仍徘徊在50%左右，这凸显了开发新型有效治疗策略的迫切需求。本研究聚焦于髓样细胞白血病1（Mcl-1）——一种在多种人类癌症中公认的致癌驱动因子，并通过体外和体内实验系统性地探索了橄榄苦苷（Ole）的治疗潜力。研究发现Ole以剂量依赖性方式抑制OSCC细胞活力。机制研究表明，Ole通过抑制Akt-GSK3β-Mcl-1通路并增强β-TRCP与Mcl-1的协同作用，促进β-TRCP介导的Mcl-1泛素化，最终导致Mcl-1降解。此外，敲低β-TRCP可减弱Ole对OSCC细胞的抑制作用。与细胞实验结果一致的是，动物实验表明Ole治疗能显著延缓肿瘤生长，且不对重要器官产生毒性。值得注意的是，无论是单独使用还是联合放疗，Ole都能有效克服OSCC细胞的放疗抗性。我们的研究结果表明，Ole是一种通过靶向Mcl-1治疗OSCC的潜在抗肿瘤制剂。

原文链接：

Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity