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Mechanisms of autophagy and endoplasmic reticulum stress in the reversal of platinum resistance of epithelial ovarian cancer cells by naringin

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Abstract

Objective

Our previous studies showed that naringin (Nar) can effectively reverse the cisplatin resistance of ovarian cancer cells. This study aims to explore the potential mechanism by which Nar reverses cisplatin resistance in ovarian cancer.

Methods

The proliferative activity of cells was evaluated using CCK8 and cell clone formation assays. Autophagic flux in cells was evaluated via LC3B immunofluorescence and monodansylcadaverine (MDC) staining. The expression levels of autophagy, endoplasmic reticulum (ER) stress, and apoptosis-related proteins were detected via Western blotting. Autophagy and ER stress were regulated using siATG5, siLC3B, rapamycin (Rap), chloroquine (CQ), 4-phenylbutyric acid (4-PBA), and thapsigargin (TG). siATG5 and siLC3B are short interfering RNAs (siRNAs) used to knock down the expression of ATG5 and LC3B genes, respectively.

Results

Nar inhibited autophagy in SKOV3/DDP cells by activating the PI3K/AKT/mTOR pathway. And Nar increased the levels of ER stress-related proteins, namely, P-PERK, GRP78, and CHOP, and promoted apoptosis in SKOV3/DDP cells. Moreover, treatment with the inhibitor of ER stress alleviated apoptosis induced by Nar in SKOV3/DDP cells. In addition, compared to cisplatin or naringin alone, the combination of Nar and cisplatin significantly reduced the proliferative activity of SKOV3/DDP cells. And siATG5, siLC3B, CQ or TG pretreatment further inhibited the proliferative activity of SKOV3/DDP cells. Conversely, Rap or 4-PBA pretreatment alleviated the cell proliferation inhibition caused by Nar combined with cisplatin.

Conclusion

Nar not only inhibited the autophagy in SKOV3/DDP cells by regulating the PI3K/AKT/mTOR signalling pathway, but also promoted apoptosis in SKOV3/DDP cells by targeting ER stress. Nar can reverse the cisplatin resistance in SKOV3/DDP cells through these two mechanisms.

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Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author on reasonable request.

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Funding

This study was funded by National Natural Science Foundation of China (Grant numbers [82060477]), Natural Science Foundation of Jiangxi Province (Grant numbers [20202BAB206054]), Science and Technology Plan of Jiangxi Provincial Health Commission in 2021 (Grant numbers [202120072]), Nanchang Advantage science and technology Innovation team construction Plan project (Hongke Zi (2019) No.228-15), Nanchang high-level scientific and technological innovation talents“Double Hundred Plan”project (Hongke Zi (2021) No. 156-29), General project of Traditional Chinese Medicine Science and Technology Plan of Jiangxi Province in 2021 (Grant numbers [2021B666]), Nanchang Science and Technology Bureau Science and technology support project (Hongke Zi (2019) No.258-6), and Nanchang City medical health science and technology support project key project (Hongke Zi (2021) No.129-1) and Jiangxi Province Graduate Students Innovation Special Fund project in 2022(Grant numbers [YC2022-B069]).

Author information

Author notes

  1. Jun Gao and Hong Zhu are co-corresponding authors.

Authors and Affiliations

  1. The Third Affiliated Hospital of Nanchang University, The First Hospital of Nanchang City, Nanchang, Jiangxi, China

    Jun Zhu, Shixin Lin & Yanlan Liu

  2. Department of Gynecologic Oncology, Jiangxi Cancer Hospital, Nanchang, Jiangxi, China

    Xia Zou, Xintong Chen, Xiaorong Yang, Jun Gao & Hong Zhu

  3. Jiangxi Provincial Key Laboratory of Tumor Metastasis and Precision Therapy, Nanchang, Jiangxi, China

    Jun Zhu & Shixin Lin

  4. Nanchang Key Laboratory of Precision Therapy for Gynecological Neoplasms, Nanchang, Jiangxi, China

    Jun Zhu, Shixin Lin & Jun Gao

Authors
  1. Jun Zhu
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  3. Xia Zou
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  4. Xintong Chen
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  5. Yanlan Liu
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  8. Hong Zhu
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Contributions

All authors contributed to the study conception and design. Material preparation,were performed by [JZ], [XC] and [XY] data collection and analysis were performed by [JZ], [SL], [XZ] and [YL]. Editing, visualization, supervision, funding acquisition, project administration was performed by [HZ], [JG]. The first draft of the manuscript was written by [JZ] and all authors commented on previous versions of the manuscript. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jun Gao or Hong Zhu.

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Zhu, J., Lin, S., Zou, X. et al. Mechanisms of autophagy and endoplasmic reticulum stress in the reversal of platinum resistance of epithelial ovarian cancer cells by naringin. Mol Biol Rep 50, 6457–6468 (2023). https://doi.org/10.1007/s11033-023-08558-3

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  • DOI: https://doi.org/10.1007/s11033-023-08558-3

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