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Honokiol antagonizes doxorubicin resistance in human breast cancer via miR-188-5p/FBXW7/c-Myc pathway

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Abstract

Background

Honokiol, a natural phenolic compound derived from Magnolia plants, is a promising anti-tumor compound that exerts a wide range of anti-cancer effects. Herein, we investigated the effect of honokiol on doxorubicin resistance in breast cancer.

Methods

Doxorubicin-sensitive (MCF-7 and MDA-MB-231) and doxorubicin-resistant (MCF-7/ADR and MDA-MB-231/ADR) breast cancer cell lines were treated with doxorubicin in the absence or presence of honokiol; then, the following tests were performed: flow cytometry for cell apoptosis, WST-1 assay for cell viability, qPCR and western blot for the expression of miR-188-5p, FBXW7, and c-Myc. MiR-188-5p mimic, miR-188-5p inhibitor, siFBXW7, and c-Myc plasmids were transfected into cancer cells to evaluate whether miR-188-5p and FBXW7/c-Myc signaling are involved in the effect of honokiol on doxorubicin resistance in breast cancer. A dual luciferase reporter system was used to study the direct interaction between miR-188-5p and FBXW7.

Results

Honokiol sensitized doxorubicin-resistant breast cancer cells to doxorubicin-induced apoptosis. Mechanically, upregulation of miR-188-5p was associated with doxorubicin resistance, and honokiol enhanced doxorubicin sensitivity by downregulating miR-188-5p. FBXW7 was confirmed to be a direct target gene of miR-188-5p. FBXW7/c-Myc signaling was involved in the chemosensitization effect of honokiol. Honokiol induced apoptosis in MCF-7/ADR and MDA-MB-231/ADR cells. However, FBXW7 silencing or c-Myc transfection resulted in resistance to the honokiol-induced apoptotic effect.

Conclusion

These findings suggest that downregulation of miR-188-5p by honokiol enhances doxorubicin sensitivity through FBXW7/c-Myc signaling in human breast cancer. Our study finds an important role of miR-188-5p in the development of doxorubicin resistance in breast cancer, and enriches our understanding of the mechanism of action of honokiol in cancer therapy.

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Acknowledgements

This study was supported by Natural Science Foundation of Hubei Province (Grant No. 2019CFB548) and National Nature Science Foundation of China (Grant No. 81874117 and 81974419). We would like to thank Editage (www.editage.cn) for English language editing.

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Authors and Affiliations

  1. Institute of Pathology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China

    Xianglan Yi, Liping Lou, Jun Wang, Jing Xiong & Sheng Zhou

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Contributions

Conception and design: JX, SZ. Development of methodology: JX, XY, SZ. Acquisition of data: JX, XY, LL, JW. Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): XY, JX, SZ. Writing, review, and/or revision of the manuscript: JX, SZ. Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): JX, LL. Study supervision: JX, SZ.

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Correspondence to Jing Xiong or Sheng Zhou.

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Yi, X., Lou, L., Wang, J. et al. Honokiol antagonizes doxorubicin resistance in human breast cancer via miR-188-5p/FBXW7/c-Myc pathway. Cancer Chemother Pharmacol 87, 647–656 (2021). https://doi.org/10.1007/s00280-021-04238-w

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