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

Cancer Gene Therapy volume 32, pages 793–805 (2025)Cite this article

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Abstract

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.

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Fig. 1: Oleuropein displays an inhibitory effect on OSCC cells.
Fig. 2: Ole induced apoptosis of OSCC cells and facilitated Mcl-1 polyubiquitination.
Fig. 3: Ole promoted the β-TRCP-mediated Mcl-1 degradation.
Fig. 4: β-TRCP depletion reversed the inhibitory effect of Ole on OSCC cells.
Fig. 5: Ole-induced Mcl-1 degradation depends on its ubiquitination sites.
Fig. 6: Ole triggered Mcl-1 degradation by suppressing the Akt/GSK3β pathway.
Fig. 7: Ole inhibited in vivo tumor growth.
Fig. 8: Ole possesses good tolerance in vivo.
Fig. 9: Ole overcomes radioresistance in vitro.
Fig. 10: Ole overcomes radioresistance in vivo.

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Data availability

The datasets used and analyzed in this study are available from the corresponding author (WL) upon request.

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Funding

This work was supported by the Wisdom Accumulation and Talent Cultivation Project of the Third Xiangya Hospital of Central South University (BJ202203).

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  1. These authors contributed equally: Wen Liu, Song Peng.

Authors and Affiliations

  1. Department of Radiology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, PR China

    Wen Liu, Song Peng, Jinzhuang Liao, Ruirui Wang, Pengfei Guo & Wei Li

  2. Cell Transplantation and Gene Therapy Institute, The Third Xiangya Hospital of Central South University, Changsha, Hunan, PR China

    Wen Liu, Song Peng, Jinzhuang Liao, Ruirui Wang, Pengfei Guo & Wei Li

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Contributions

Wen Liu, Song Peng, and Wei Li conceived and designed the project. Wen Liu, Song Peng, Jinzhuang Liao, Ruirui Wang, and Pengfei Guo administered the project and developed its methodology. Wen Liu, Song Peng, Jinzhuang Liao, Ruirui Wang, and Pengfei Guo analyzed and interpreted the data. Wen Liu and Song Peng wrote the original draft. Wei Li supervised the manuscript and acquired funding. All authors have read and agreed to the published version.

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Correspondence to Wei Li.

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All animal experiments were approved by the Institutional Animal Care and Use Committee, the Third Xiangya Hospital of Central South University (Changsha, China). All methods were performed in accordance with the relevant guidelines and regulations. Clinical trial number: not applicable.

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Liu, W., Peng, S., Liao, J. et al. Oleuropein regulates ubiquitination-mediated Mcl-1 turnover and exhibits antitumor activity. Cancer Gene Ther 32, 793–805 (2025). https://doi.org/10.1038/s41417-025-00921-9

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