Liu Wen, Peng Song, Liao Jinzhuang, Wang Ruirui, Guo Pengfei, Li Wei
Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, PR China.
Cancer Gene Ther. 2025 Jun 12. doi: 10.1038/s41417-025-00921-9.
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.
口腔鳞状细胞癌（OSCC）是最常见的口腔恶性肿瘤类型，在全球范围内具有较高的发病率。尽管OSCC治疗不断取得进展，但其5年生存率仍约为50%，这凸显了开发新的有效治疗策略的迫切需求。在此，我们聚焦于髓样白血病1（Mcl-1），它是多种人类癌症中著名的致癌驱动因子，并通过体外和体内分析系统地探索了橄榄苦苷（Ole）的治疗潜力。我们的研究结果表明，Ole剂量依赖性地抑制OSCC细胞活力。从机制上讲，Ole通过抑制Akt-GSK3β-Mcl-1途径并增强β-TRCP与Mcl-1之间的协作，促进β-TRCP介导的Mcl-1泛素化，最终导致Mcl-1降解。此外，β-TRCP的敲低减轻了Ole对OSCC细胞的抑制作用。与我们基于细胞的实验一致，动物研究表明，Ole治疗显著延迟肿瘤生长，且对重要器官无毒性。此外，无论单独使用还是与放疗联合使用，Ole都能有效克服OSCC细胞的放射抗性。我们的结果表明，Ole是一种有前景的抗肿瘤药物，能够通过靶向Mcl-1治疗OSCC。
