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Osthole increases the radiosensitivity of hepatoma cells by inhibiting GSK-3β/AMPK/mTOR pathway-controlled glycolysis

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Abstract

Osthole is a natural coumarin substance that has an inhibitory effect on hepatic cancer, but its radiosensitization effect on hepatoma cells has not been reported. This study aimed to investigate the effect of osthole. Human HCC-LM3 and SK-Hep-1 hepatoma cells were used and treated with or without osthole, irradiation, or their combination; the cell survival, migration, colony formation, DNA damage repair, intracellular lactic acid content, and glycolysis-related glycogen synthase kinase-3β (GSK-3β), p-GSK-3β, AMP-activated protein kinase (AMPK), p-AMPK, mammalian target of rapamycin (mTOR), p-mTOR, glucose transporter-1 (GLUT-1), GLUT-3, and pyruvate kinase isozyme type M2 (PKM2) protein expressions were determined. Compared with the irradiation group, the osthole plus irradiation group could further decrease the survival rate, migration, colony formation, and DNA damage repair of both hepatoma cells, indicating a synergistic effect of the combination treatment. Moreover, the combination of osthole and irradiation could decrease the content of intracellular lactic acid, ratios of intracellular p-GSK-3β/GSK-3β and p-mTOR/mTOR proteins, and expressions of intracellular GLUT-1/3 and PKM2 proteins, and increase the ratio of intracellular p-AMPK/AMPK proteins. Osthole can increase the radiosensitivity of hepatoma cells, and its radiosensitization mechanisms may be related to glycolytic inhibition by attenuating the GSK-3β/AMPK/mTOR pathway.

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Funding

This work was supported by the Science & Technology Project of Suzhou City for Medical Health (KJXW2020039), Research Fund of Nanjing Medical University (NMUB2020254), and Research Program of Gusu School of Nanjing Medical University (GSKY20220526), China.

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  1. Hui Huang and Jie Xue contributed equally to this work

Authors and Affiliations

  1. College of Pharmaceutical Sciences, Soochow University, Suzhou, Jiangsu Province, China

    Hui Huang, Jie Xue & Mei-Lin Xie

  2. Department of Neurosurgery, The Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Gusu School, Nanjing Medical University, Suzhou, Jiangsu Province, China

    Tao Xie

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  1. Hui Huang
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  2. Jie Xue
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Contributions

HH and XJ performed the cell experimental study. HH analyzed the experimental data and drafted the manuscript. XJ revised the manuscript. XT and XML designed the study and reviewed the manuscript. All the authors read and approved the final version of the manuscript. The authors declare that all the data were generated in-house and that no paper mill was used.

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Correspondence to Tao Xie or Mei-Lin Xie.

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Huang, H., Xue, J., Xie, T. et al. Osthole increases the radiosensitivity of hepatoma cells by inhibiting GSK-3β/AMPK/mTOR pathway-controlled glycolysis. Naunyn-Schmiedeberg's Arch Pharmacol 396, 683–692 (2023). https://doi.org/10.1007/s00210-022-02347-8

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