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Micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in tumor cells in an USP7/AKT/GSK-3β pathway-dependent manner

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Abstract

Breast cancer and osteosarcoma are common cancers in women and children, respectively, but ideal drugs for treating patients with breast cancer or osteosarcoma remain to be found. Micafungin is an antifungal drug with antitumor activity on leukemia. Based on the notion of drug repurposing, this study aims to evaluate the antitumor effects of micafungin on breast cancer and osteosarcoma in vitro and in vivo, and to elucidate the underlying mechanisms. Five breast cancer cell lines (MDA-MB-231, BT-549, SK-BR-3, MCF-7, and 4T1) and one osteosarcoma cell line (143B) were chosen for the in vitro studies. Micafungin exerted an inhibitory effect on the viability of all cell lines, and MCF-7 cells were most sensitive to micafungin among the breast cancer cell lines. In addition, micafungin showed an inhibitory effect on the proliferation, clone formation, and migration in MCF7 and 143B cells. The inhibitory effect of micafungin on the growth of breast cancer and osteosarcoma was further confirmed with xenograft tumor mouse models. To explore the underlying mechanisms, the effect of micafungin on epithelial-mesenchymal transition (EMT) was examined. As expected, the levels of matrix metalloproteinase 9 and vimentin in MCF-7 and 143B cells were notably reduced in the presence of micafungin, concomitant with the decreased levels of ubiquitin-specific protease 7 (USP7), p-AKT, and p-GSK-3β. Based on these observations, we conclude that micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in an USP7/AKT/GSK-3β pathway-dependent manner.

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Data will be made available on request.

Abbreviations

CDK4/6:

Cyclin-dependent kinase 4/6

PD-L1:

Programmed cell death ligand 1

PI3K:

Phosphatidylinositol 3-kinase

EMT:

Epithelial-mesenchymal transition

MMP9:

Matrix metalloproteinase 9

USP7:

Ubiquitin‑specific protease 7

GSK3β:

Glycogen synthase kinase 3β

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Funding

This work was supported by the National Natural Science Foundation of China (No. 82073849 to **u-Ju Luo), and the Natural Science Foundation of Hunan Province, China (No. 2021JJ30032 to **u-Ju Luo).

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Authors and Affiliations

  1. Department of Laboratory Medicine, The Third **angya Hospital of Central South University, Changsha, 410013, China

    Qian-Lin Wang, Li Wang, Qiong-Yu Li, Hui-Yin Li, Dan Wei, **-Yun Xu & **u-Ju Luo

  2. Department of Laboratory Medicine, Changsha Blood Central, Changsha, 410005, China

    Qian-Lin Wang

  3. Department of General Surgery, **angya Hospital, Central South University, Changsha, 410008, China

    Ling Lin

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  1. Qian-Lin Wang
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  2. Li Wang
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  6. Dan Wei
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Contributions

L.X.J. and X.J.Y. conceived and designed the study. W.Q.L., W.L., L.Q.Y., and L.H.Y. conducted the experiments. W.Q.L., W.L., L.L., and W.D. analyzed the data. L.X.J., X.J.Y., and W.Q.L. wrote the manuscript. All authors read and approved the manuscript. The authors declare that all data were generated in-house and no paper mill was used.

Corresponding authors

Correspondence to **-Yun Xu or **u-Ju Luo.

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Ethical statement

Animal experiments were conducted in accordance with the local ethics committee (2020sydw0931, the Department of Laboratory Animals of Central South University). The treatment of animals in all experiments conforms to the ethical standards of experimental animals.

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The authors declare no competing interests.

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Qian-Lin Wang and Li Wang contributed equally to this work.

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Wang, QL., Wang, L., Li, QY. et al. Micafungin exerts antitumor effect on breast cancer and osteosarcoma through preventing EMT in tumor cells in an USP7/AKT/GSK-3β pathway-dependent manner. Naunyn-Schmiedeberg's Arch Pharmacol 397, 4447–4459 (2024). https://doi.org/10.1007/s00210-023-02903-w

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